Therapeutically active 2-aminoalkylthio-3H-1.5-benzodiazepines and process for preparing them

ABSTRACT

Novel derivatives of 3H-1,5-benzodiazepine and of their salts of addition with acids, including their quaternary ammonium salts, having the general formula: ##EQU1## are provided. Such compounds are effective therapeutically against a large spectrum of gram positive bacteria and APR8 influenza virus. The invention also provides a novel method of preparing compounds having the formula: ##EQU2## wherein R and R&#39; are the same as above, by reacting orthophenylenediamine with a benzoyldithioacetic acid having the formula: ##EQU3## wherein R and R&#39; are as defined above.

This invention relates generally to therapeutically active derivatives of 3H-1,5-benzodiazepine and more particularly to compounds of the following formula and to the acid salts and quaternary ammonium salts of such compounds: ##EQU4## wherein: R represents hydrogen, halogen, methoxy, phenylthio or alkylthio group having a straight or branched chain, which may contain 1 to 12 carbon atoms;

R¹ represents hydrogen, halogen, methyl, phenyl, phenoxy or alkylthio group having a straight or branched chain, which may contain 1 to 12 carbon atoms, cyclohexylthio, benzylthio or phenylthio;

R² represents di-lower alkyl-amino group, or a substituted or unsubstituted penta- or hexa-atomic saturated cyclic amino group which, besides the nitrogen atom, by which it is bound to X, may also contain another hetero-atom;

X represents a straight or branched alkylene chain containing 2 or 3 carbon atoms.

It is therefore an object of this invention to provide compounds of Formula I. Another object of the invention is to provide a novel method of making compounds of formula III' and of formula III hereinafter set forth.

The products of formula I have a considerable antibacterial activity against a large spectrum of gram positive bacterial, and an anti-virus activity against the APR8 influenza virus and are useful for therapeutic purposes. Particularly preferred compounds are 2,beta,N-diethylaminoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine iodomethylate and 2,beta,N-diethylamineoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine methyl nitrate.

According to the invention, the compounds having the formula I are prepared by successive steps which are shown in the following diagram:

The starting products for this synthesis are the benzoyldithioacetic acids having the formula ##EQU5## which may also exist in the tautomer form of 1-phenyl-3,3-dimercapto-2-propene-1-ones having the formula ##EQU6## wherein R and R¹ are as defined above. Some of these products are already known (C. Kelber - Ber. 43, 2 (1910); G. Kelber et al Ber. 45, 137 (1912); A. Thuillier et al - Bull. Soc. Chim. Fr. 1398 (1959)).

The compounds having the formulas II and II' can be prepared by reacting the corresponding acetophenone with carbon disulfide in the presence of sodium ter. amylate.

According to the invention the compound having the formula III is obtained by heating benzoyldithioacetic acid having the formula II and o-phenylenediamine in a polar or nonpolar solvent, for example, dioxane, ethyl alcohol, benzene, toluene, xylene or even water with elimination of water and hydrogen sulfide: ##EQU7##

These products may also exist in the tautomer form III', for example, in the presence of NaH and in such case they may supply alkylthioderivatives: ##EQU8##

The foregoing process for preparing the compounds having the formula III is new and provided by the invention. It is known indeed that the benzodiazepinthiones are obtained by treating the corresponding benzodiazepinones with phosphorus pentasulfide.

For the introduction of the dialkylaminoalkyl group --X--R², the compounds having the formula III, are mixed with an equimolecular quantity of sodium hydride and then are treated with the corresponding dialkylaminoalkylhalide having the formula Hal-X-R², wherein X and R² are as defined above with respect to formula I and Hal represents a halogen such as chlorine, bromine in a solvent such as ethyl ether, benzene, toluene, etc., and the mixture is heated between 40°C and 130°C for a period ranging from 5 to 20 hours. After elimination of sodium halide by filtration, the solvent and the possible excess of aminoalkyl halide are removed by distillation under reduced pressure, and the products having the formula I are obtained as a free base. In most cases they are obtained as an oily residue which can be purified by crystallization (generally petroleum ether or ligroine).

Conventional methods are used to prepare the salts of addition with the acids and to prepare the quanternary ammonium salts; in particular, the latter compounds can be obtained by treating the compounds of formula I with alkyl or aralkyl halide in acetone, isopropanol or ethanol at room temperature for a period of time ranging from 15 to 96 hours until complete precipitation.

The quaternary ammonium salts may also be obtained starting from the ammonium halides obtained as said hereinabove.

One method consists in effecting a double exchange between the methyl ammonium iodide and a soluble silver salt, for example, silver nitrate, so as to obtain in this way the corresponding methyl nitrate.

Another method consists in passing a methylammonium halide solution through a column of anionic exchanger resin (OH⁻), to free the quaternary ammonium hydroxide, and in neutralizing the latter with the theoretical quantity of acid.

The preparation of compounds having formula I may be represented by the following: ##EQU9##

The preparation of the quaternary ammonium salts may be represented as follows: ##SPC1##

The preparation of the intermediate compounds having the formula II or II' and III or III' is illustrated by the following examples.

EXAMPLE 1 4-phenoxy-benzoyldithioacetic acid (Formula II wherein R = H and R¹ = C₆ H₅ O-)

A solution of 5.30 g of 4-acetyldiphenylether and of 1.90 g of carbon disulfide in 6 ml of benzene is added dropwise in 2.5 hours at 15°C to 50 ml of a molar benzene solution of sodium ter-amylate. The reaction mixture is then kept at 15°C for 30 min. and poured into icy water. The mixture is separated and the benzene layer is removed. The aqueous solution is washed twice with ethyl ether which is then removed. The solution is cooled, and acidified with cold diluted H₂ SO₄. The precipitate is filtered, washed with water, and dried in a desiccator over NaOH - P₂ O₅. Yield, 6.15 g; m.p. 78°C.

    ______________________________________                                         Analysis for C.sub.15 H.sub.12 O.sub.2 S.sub.2                                                 C      H       S                                               ______________________________________                                                     calc. %                                                                              62.50    4.20    21.73                                                  found. %                                                                              62.15    4.11    22.20                                       ______________________________________                                    

EXAMPLE 2 4-phenylthio-benzoyldithioacetic acid (Formula II wherein R = H and R¹ = C₆ H₅ S-)

A solution of 5.7 g of 4-acetyl-diphenylsulfide in 6 ml of benzene and 1.90 g of carbon disulfide is added dropwise in 2.5 hours to 50 ml of a molar benzene solution of sodium ter. amylate cooled to 15°C and the reaction is further carried out as in Example 1. Yield 7.15 g, m.p. 90°C.

    ______________________________________                                         Analysis for C.sub.15 H.sub.12 OS.sub.3                                                        C      H       S                                               ______________________________________                                                     calc. %                                                                              59.21    3.98    31.50                                                  found. %                                                                              58.89    4.22    31.52                                       ______________________________________                                    

EXAMPLE 3 4-phenyl-1.3-dihydro-2H-1.5-benzodiazepine-2-thione (Formula III wherein R and R¹ = H)

A mixture of 1.08 g of o-phenylendiamine, 10 ml of xylene and 1.96 g of benzoyldithioacetic acid (Thuillier et al - Bull. Soc. Chim. Fr. 1938 (1959) is refluxed for 1 hour under a stream of nitrogen. The reaction may also be carried out in water, alcohol or dioxane. After cooling, the precipitate is filtered, washed with ethyl ether, and crystallized from ethyl acetate. Yield 2 g, m.p. 228°-230°C.

    ______________________________________                                         Analysis for C.sub.15 H.sub.12 N.sub.2 S                                                   C      H       N        S                                          ______________________________________                                                 calc. %                                                                              71.41    4.80    11.11  12.69                                           found. %                                                                              71.44    5.24    11.14  13.00                                    ______________________________________                                    

EXAMPLE 4 4,p-chlorophynyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione

(Formula III wherein R = H and R¹ = p-Cl)

A mixture of 1.08 g of o-phenylendiamine, 40 ml toluene and 2.14 g of 4-chorophenyl-benzoyldithioacetic acid (Thuillier et al. - Bull. Soc. Chim. Fr. 1398 (1959) ) is refluxed for 1 hour under a stream of nitrogen. After cooling, the precipitate is filtered, washed with ethyl ether, and crystallized from ethyl acetate. Yield 2.1 g, m. p. 243°-245°C.

    ______________________________________                                         Analysis for C.sub.15 H.sub.11 ClN.sub.2 S.sub.2                                           C      H       N       S                                           ______________________________________                                                 calc. %                                                                              62.84    3.86    9.77  11.16                                            found. %                                                                              62.92    4.16    9.72  11.28                                     ______________________________________                                    

EXAMPLE 5 4,p-diphenylyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione

(Formula III wherein R = H and R¹ = p-C.sub. 6 H₅)

A mixture of 1.08 g of o-phenylendiamine, 40 ml of toluene and 2.72 g of 4-phenyl-benzoyldithioacetic acid (Thuillier et al. - Bull. Soc. Chim. Fr. 1398 (1959) ) is refluxed for 1 hour under a stream of nitrogen. After cooling, the precipitate is filtered, washed with ethyl ether, and crystallized from ethyl acetate. Yield 2.4 g, m. p. 229°-230°C.

    ______________________________________                                         Analysis for C.sub.21 H.sub.16 N.sub.2 S                                                   C      H       N       S                                           ______________________________________                                                 calc. %                                                                              76.81    4.91    8.53  9.75                                             found. %                                                                              76.65    4.86    8.78  9.86                                      ______________________________________                                    

EXAMPLE 6 4,p-phenoxyphenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione

(Formula III wherein R = H and R¹ = C₆ H₅ O)

A mixture of 1.44 g of 4-phenoxy-benzoyldithioacetic acid, 0.54 g of o-phenylediamine and 20 ml of xylene is refluxed for 1.5 hours under a stream of nitrogen. Then the mixture is cooled and the resulting crystalline precipitate is filtered and re-crystallized from ethyl acetate. Yield 0.86 g, m. p. 225°C.

    ______________________________________                                         Analysis for C.sub.21 H.sub.16 N.sub.2 OS                                                  C      H       N       S                                           ______________________________________                                                 calc. %                                                                              73.24    4.68    8.14  9.29                                             found. %                                                                              73.27    4.74    8.02  9.45                                      ______________________________________                                    

EXAMPLE 7 4,p-phenylthiophenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione

(Formula III wherein R = H and R¹ = C₆ H₅ S)

A mixture of 1.08 g of o-phenylendiamine, 20 ml of toluene and 3.04 g of 4-phenylthio-benzoyldithioacetic acid is refluxed for 1 hour. After cooling, the mixture is filtered, the precipitate is washed with ethyl ether, and crystallized from ethyl acetate. Yield 1.8 g, m. p. 229°-230°C.

    ______________________________________                                         Analysis for C.sub.21 H.sub.16 N.sub.2 S.sub.2                                             C      H       N       S                                           ______________________________________                                                 calc. %                                                                              69.99    4.48    7.77  17.76                                            found. %                                                                              69.85    4.68    7.53  17.51                                     ______________________________________                                    

The preparation of the compounds having the formula I by the process according to the invention is illustrated by the following examples.

EXAMPLE 8 2,gamma,N(N'-methyl)piperazinopropylthio-4-phenyl-3H-1,5-benzodiazephine.2HCl

(Formula I wherein R and R¹ = H; ##EQU10## and X = -CH₂ -CH₂ -CH₂ -)

A mixture of 10.08 g of 4-phenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione, 2 g of 50 percent sodium hydride in oil and 800 ml of benzene is refluxed for 30 minutes. A solution of 10.4 g of gamma, N'-methyl-N-piperazinopropyl chloride in 20 ml of benzene is then added dropwise in 5 minutes. The mixture is refluxed for 10 hours. Then the mixture is cooled and filtered. The filtrate is evaporated to dryness in vacuo at 20°-30°C. The obtained oil is treated with boiling petroleum ether to separate the insoluble product. After filtration the filtrate is evaporated to dryness. The residue is washed with water until the gamma,N'-methyl-N-piperazinopropyl chloride disappears (TLC). The oil is then dissolved in isopropanol and neutralized with HCl in isopropanol to obtain the dihydrochloride. The crystals are filtered and recrystallized from isopropanol. Yield 7.6 g, m. p. 228°C.

    ______________________________________                                         Analysis for C.sub.23 H.sub.28 N.sub.4 S.2HCl                                              C      H       N        S                                          ______________________________________                                                 calc. %                                                                              59.34    6.49    12.04  6.87                                            found. %                                                                              59.04    6.73    11.63  7.23                                     ______________________________________                                    

EXAMPLE 9 2,gamma,N'-methyl-N-piperazine-n-propylthio-4-phenyl-3H-1,5-benzodiazepine monoiodomethylate

(Formula I wherein R and R¹ = H; ##EQU11## and X = -CH₂ CH₂ CH₂ -)

1.42 g of methyl iodide are added to a solution cooled to 0°C of 3.92 g of 2, gamma,N'-methyl-N-piperazino-n-propylthio-4-phenyl-3H-1,5-benzodiazepine in 25 ml of acetone. The mixture is kept at 0°C for 24 hours.

Separated crystals are filtered and recrystallized from methanol. After filtration of 0.25 g of the bis-iodomethylate which is crystallized, the monoiodomethylate is obtained by concentration of the solution to a small volume. Yield 3.47 g, m. p. 167°C.

    ______________________________________                                         Analysis for C.sub.24 H.sub.31 IN.sub.4 S                                       calc. %  53.93    5.84    10.48  23.75  5.98                                  found. %  54.36    5.71    10.24  23.62  6.24                                  ______________________________________                                    

EXAMPLE 10 2, gamma,N'-methyl-N-piperazinpropylthio-4-phenyl-3H-1,5-benzodiazepine bis-iodomethylate

(Formula I wherein R and R¹ = H; ##EQU12## and X = -CH₂ CH₂ CH₂ -)

6.39 g of methyl iodide are added to a solution of 5.88 g of 2,gamma-N'-methyl-N-piperazinopropylthio-4-phenyl-3H-1,5-benzodiazepine in 60 ml of acetone. The mixture is kept at 20°-30°C for 40 hours. It is observed that the product crystallizes. The crystals are filtered and recrystallized from methanol.

Yield 7.3 g, m. p. 226°C

    ______________________________________                                         Analysis for C.sub.25 H.sub.31 I.sub.2 N.sub.4 S                                       C      H       N        J      S                                       ______________________________________                                         calc. %   44.39    5.06    8.28   37.52  4.73                                  found %   44.66    5.36    8.34   38.12  5.06                                  ______________________________________                                    

EXAMPLE 11 2,gamma,N-dimethylaminopropylthio-4-phenyl-3H-1,5-benzodiazepine.HCl

(Formula I wherein R and R¹ = H; R² = N(CH₃)₂ and X = -CH₂ -CH₂ -CH₂ -)

A mixture of 5.04 g of 4-phenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione, 1 g of 50 percent sodium hydride in oil and 400 ml of anhydrous ethyl ether is refluxed for 30 minutes, then a solution of 3.63 g of gamma,N-dimethylaminopropyl chloride in 10 ml of anhydrous ethyl ether is added dropwise in 5 minutes.

The mixture is refluxed for 10 hours. After cooling the precipitate is filtered. The filtrate is evaporated to dryness, the residue is dissolved in petroleum ether and the insoluble fraction is separated by filtration.

The solvent is evaporated in vacuo and the residue is heated to 50°/0.1 mm Hg until the excess of gamma,N-dimethylaminopropyl chloride is removed.

The oil is then dissolved in isopropanol and neutralized with HCl in isopropanol.

By cooling the hydrochloride crystallizes with one molecule of isopropyl alcohol. The crystals are recrystallized from isopropyl alcohol.

Yield 5.1 g, m. p. 80°C.

    ______________________________________                                         Analysis for C.sub.20 H.sub.23 N.sub.3 S.HCl.C.sub.3 H.sub.8 O                         C      H       N       S     C.sub.3 H.sub.7 O                         ______________________________________                                          calc. %  63.65    7.43    9.68  7.37  13.61                                   found. %  63.68    7.42    9.60  7.71  13.42                                   ______________________________________                                    

EXAMPLE 12 2,gamma,N-dimethylaminopropylthio-4-phenyl-3H-1,5-benzo-diazepine iodomethylate

(Formula I wherein R and R¹ =H; R² = N(CH₃)₂ and X = -CH₂ -CH₂ -CH₂ -)

2.13 g of methyl iodide are added to a solution of 3.37 g of 2,gamma,N-dimethylaminopropylthio-4-phenyl-3H-1,5-benzodiazepine in 20 ml of acetone and the mixture is kept at 20°-30° for 60 hours. The crystals are filtered and recrystallized from isopropyl alcohol.

    ______________________________________                                         Analysis for C.sub.21 H.sub.26 N.sub.3 SI                                              C      H       N        S     I                                        ______________________________________                                         calc. %   52.61    5.34    8.76   6.67  26.47                                  found %   52.89    5.69    8.67   6.85  25.94                                  ______________________________________                                    

EXAMPLE 13 2,gamma,N-pyrrolidinopropylthio-4,p-chlorophenyl-3H-1,5-benzodiazepine.sup.. HCl

(Formula I wherein R = H; R¹ = p-Cl;

R² = N

and X = -CH₂ -CH₂ -CH₂ -)

One gram of 50 percent sodium hydride in oil is added to 5.72 g of 4,p-chlorophenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione in 400 ml of anhydrous benzene and refluxed for 30 minutes. The obtained sodium salt is refluxed for 10 hours with 4.42 g of 1,N-pyrrolidino-3-chloropropane in 15 ml of benzene. After filtration the solvent is evaporated. The excess of 1,N-pyrrolidino-3-chloropropane is removed by distillation at 60°/0.2 mm Hg in a stream of nitrogen. The residue is crystallized from petroleum ether. Yield 5.6 g, m. p. 73-74°C.

    ______________________________________                                         Analysis for C.sub.22 H.sub.24 N.sub.3 ClS                                             C      H       N        Cl     S                                       ______________________________________                                          calc. %  66.40    6.08    10.56  8.91   8.06                                  found. %  66.61    6.17    10.42  9.24   8.00                                  ______________________________________                                    

The hydrochloride is prepared by neutralizing with HCl in isopropanol an isopropanol solution of the base and was crystallized from isopropanol. Yield 4.35 g, m. p. 193-194°C.

    ______________________________________                                         Analysis for C.sub.22 H.sub.24 N.sub.3 ClS.HCl                                         C      H       N        Cl     S                                       ______________________________________                                          calc. %  60.97    5.81    9.69   16.38  7.41                                  found. %  60.92    5.48    9.68   16.57  7.24                                  ______________________________________                                    

EXAMPLE 14 2,gamma,N-pyrrolidinopropylthio-4,p-chlorophenyl-3H-1.5-benzodiazepine iodomethylate

(Formula I wherein R = H; R¹ = p-Cl;

R² = N

and X = -CH₂ -CH₂ -CH₂ -)

0.213 g of methyl iodide are added to a solution of 0.397 g of 2,gamma-N-pyrrolidinopropylthio-4,p-chlorophenyl-3H-1.5-benzodiazepine in 20 ml of isopropanol. After 15 hours at room temperature the product crystallizes. After cooling the crystals are filtered and crystallized from ethanol. Yield 0.425 g, m. p. 156-157°C.

    ______________________________________                                         Analysis for C.sub.23 H.sub.27 N.sub.3 SClI                                            C      H       H        I      S                                       ______________________________________                                         calc. %   51.16    5.04    7.78   23.51  5.94                                  found %   51.05    4.70    7.56   23.35  6.26                                  ______________________________________                                    

EXAMPLE 15 2,beta,N-pyrrolidinoethylthio-4,p-chlorophenyl-3H-1,5-benzodiazepine

(Formula I wherein R = H; R¹ = p-Cl;

R² = N

and X = -CH₂ -CH₂ -).

2.5 g of a 50 percent oily suspension of sodium hydride is added to a solution of 8.6 g of 4,p-chlorophenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione in 600 ml of anhydrous benzene and refluxed for 30 minutes. The obtained sodium salt is refluxed for 10 hours with 6 g of 1,N-pyrrolidino-2-chloroethane. The mixture is filtered and the solvent is evaporated. After heating for 2 hours at 60°C/0.2 mm Hg under a stream of nitrogen to remove the 1,N-pyrrolidino-2-chloroethane, the residue is crystallized from petroleum ether. Yield 8.39 g, m. p. 76°C.

    ______________________________________                                         Analysis for C.sub.21 H.sub.22 N.sub.3 ClS                                             C      H       N        Cl     S                                       ______________________________________                                         calc. %   65.70    5.77    10.95  9.24   8.35                                  found %   65.92    5.51    10.79  9.65   8.19                                  ______________________________________                                    

The hydrochloride is prepared by acidifying the base in an isopropanol solution and it is crystallized from isopropanol; m. p. 224°C.

    ______________________________________                                         Analysis for C.sub.21 H.sub.22 N.sub.3 SCl.HCl                                         C      H       N        Cl     S                                       ______________________________________                                         calc. %   60.00    5.51    9.99   17.26  7.63                                  found %   59.75    5.70    9.72   17.42  7.52                                  ______________________________________                                    

EXAMPLE 16 2,β,N-pyrrolidinoethylthio-4,p-chlorophenyl-3H-1,5-benzodiazepine iodomethylate

(Formula I wherein R = H; R¹ = p-Cl;

R² = N

and X = -CH₂ -CH₂ -)

0.213 g of methyl iodide are added to a solution of 0.383 g of 2,beta,N-pyrrolidinoethylthio-4,p-chlorophenyl-3H-1, 5-benzodiazepine in 20 ml of isopropanol. After about 15 hours at room temperature, an oil is separated; the solvent is decanted and a part of the product is crystallized therefrom. The oily residue is treated with isopropanol up to solidification.

After cooling and filtering the products are collected together and are crystallized from ethanol. Yield 0.6 g; m. p. 190-191°C.

    ______________________________________                                         Analysis for C.sub.22 H.sub.25 N.sub.3 SClI                                            C      H       N       I       S                                       ______________________________________                                         calc. %   50.24    4.79    7.99  24.13   6.09                                  found %   49.99    4.49    7.78  24.15   6.41                                  ______________________________________                                    

EXAMPLE 17 2,beta,N-diethylaminoethylthio-4,p-chlorophenyl-3H-1,5-benzodiazepine.sup.. HCl

(Formula I wherein R = H; R¹ = p-Cl; R² = N(C₂ H₅)₂ and X=-CH₂ -CH₂ -)

A mixture of 2.52 g of 4,p-chlorophenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione, 0.50 g of 50 percent sodium hydride in oil and 200 ml of benzene is refluxed for 30 minutes, then a solution of 2.02 g of beta-diethylaminoethylchloride in 7 ml of benzene is added dropwise over 5 minutes.

The mixture is refluxed for 10 hours. After cooling the sodium chloride is filtered off. The filtrate is evaporated in vacuo at 30°C. The oily residue is dissolved in petroleum ether and a small insoluble amount of product is filtered. (0.400 g of starting product m. p. 235°C.) The solution is evaporated to dryness in vacuo. The residue is heated to 50° in vacuo to remove the excess of beta-diethylaminoethyl-chloride. The oily residue is then dissolved in isopropanol and acidifying with HCl in isopropanol. The product is crystallized by addition of anhydrous ethyl ether to the solution. Yield 3.08 g, m. p. 159°C.

    ______________________________________                                         Analysis for C.sub.21 H.sub.24 ClN.sub.3 S.HCl                                         C      H       N       S                                               ______________________________________                                         calc. %   59.71    5.96    9.94  7.57                                          found %   59.73    5.94    9.81  7.32                                          ______________________________________                                    

EXAMPLE 18 2,beta,N-diethylaminoethylthio-4,p-chlorophenyl-3H-1,5-benzodiazepine iodomethylate.

(Formula I wherein R = H; R¹ = p-Cl; R² = N(C₂ H₅)₂ and X = -CH₂ -CH₂ -)

2.13 g of methyl iodide are added to a solution of 3.85 g of 2,beta,N-diethylaminoethylthio-4,p-chlorophenyl-3H-1,5-benzodiazepine in 35 ml of acetone. The mixture is kept at 20°-30° for 60 hours, then is cooled, filtered and crystallized from acetone. Yield 4.5 g, m. p. 182°C.

    ______________________________________                                         Analysis for C.sub.22 H.sub.27 N.sub.3 ClIS                                            C      H       N       S      I                                        ______________________________________                                         calc. %   50.05    5.15    7.96  6.06   24.04                                  found %   50.38    5.20    8.11  6.44   24.03                                  ______________________________________                                    

EXAMPLE 19 2,gamma,N-diethylaminopropylthio-4,p-chlorophenyl-3H-1,5-benzodiazepine.sup.. HCl

(Formula I wherein R = H; R¹ = p-Cl; R² = N(C₂ H₅)₂ and X = -CH₂ -CH₂ -CH₂ -)

8.6 g of 4,p-chlorophenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione in 600 ml of anhydrous benzene are refluxed for 30 minutes with 1.5 g of sodium hydride in a 50 percent oily suspension. To the mixture 6.2 g of 1-diethylamino-3-chloropropane is added and refluxed for 10 hours. The mixture is filtered, the solvent is evaporated and the residue is heated for 2 hours at 60°C/0.2 mm Hg in a stream of nitrogen to remove the excess of 1-diethylamino-3-chloropropane. The residue is dissolved in petroleum ether and filtered with charcoal; the solvent is evaporated and the residue is dissolved in isopropanol and neutralized with HCl in isopropanol. The hydrochloride is filtered and crystallized from ethyl acetate. Yield 8.0 g, m. p. 159-160°C.

    ______________________________________                                         Analysis for C.sub.22 H.sub.26 N.sub.3 ClS.HCl                                         C      H       N       Cl      S                                       ______________________________________                                         calc. %   60.55    6.24    9.63  16.35   7.53                                  found %   60.33    6.41    9.63  16.10   7.09                                  ______________________________________                                    

EXAMPLE 20 2,gamma,N-diethylaminopropylthio-4,p-chlorophenyl-3H-1,5-benzodiazepine iodomethylate

(Formula I wherein R = H; R¹ = p-Cl; R² = N(C₂ H₅)₂ and X = -CH₂ -CH₂ -CH₂ -)

0.213 g of methyl iodide are added to 0.399 g of 2,gamma,N-diethylamiopropylthio-4,p-chlorophenyl-3H-1,5-benzodiazepine in 10 ml of ethanol. The mixture is kept for 4 days at room temperature. After cooling the precipitate is collected and crystallized twice from ethanol. Yield 0.26 g, m. p. 162°C.

    ______________________________________                                         Analysis for C.sub.23 H.sub.29 N.sub.3 SClI                                            C      H       N       I       S                                       ______________________________________                                         calc. %   50.97    5.39    7.75  23.42   5.91                                  found %   51.13    5.31    7.63  23.58   6.27                                  ______________________________________                                    

EXAMPLE 21 2,beta,N-diethylaminothylthio-4,m-chlorophenyl-3H-1,5-benzodiazepine.sup.. HCl

(Formula I wherein R = H; R¹ = m-Cl; R² = N(C₂ H₅)₂ and X = -CH₂ -CH₂ -)

One gram of sodium hydride in a 50 percent oily suspension is added to a solution of 5.74 g of 4,m-chlorophenyl-1,3-dihydro-2H-1,-5-benzodiazepine-2-thione (prepared in a similar way as 4,p-chlorophenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione, Example 4) in 400 ml of benzene. To the suspension of sodium salt, obtained by refluxing for 30 minutes, 4.05 g of diethylaminochloroethane is added and refluxed for 10 hours. After filtering, the solvent is evaporated. The residue is heated for 2 hours at 60°C/0.2 mm Hg in a stream of nitrogen to remove the excess of diethylaminochloroethane. The residual oil is dissolved in petroleum ether and filtered with charcoal; the solvent is evaporated and the residue is treated with isopropyl alcohol and acidified with HCl in isopropanol. After one night at room temperature, the hydrochloride crystallizes. After cooling, the crystals are filtered and crystallized from ethyl acetate.

Yield 5.61 g, m. p. 149°-150°C.

    ______________________________________                                         Analysis for C.sub.21 H.sub.24 N.sub.3 SCl.HCl                                         C      H       N       Cl      S                                       ______________________________________                                         calc. %   59.71    5.97    9.95  16.78   7.59                                  found %   60.04    5.73    9.98  16.73   7.66                                  ______________________________________                                    

EXAMPLE 22 2,beta,N-diethylaminoethylthio-4,m-chlorophenyl-3H-1,5-benzodiazepine iodomethylate

(Formula I wherein R = H; R¹ = m-Cl; R² = N(C₂ H₅)₂ and X = -CH₂ CH₂ -)

0.213 g of methyl iodide are added at 20°C to a solution of 0.385 g of 2,beta,N-diethylaminoethylthio-4,m-chlorophenyl-3H-1,5-benzodiazepine in 4 ml of acetone. After 48 hours at 20°C, the mixture is cooled and filtered.

Yield 0.357 g; m. p. 177°-178°C. The product is crystallized from ethanol.

    ______________________________________                                         Analysis for C.sub.22 H.sub.27 N.sub.3 SCl.I                                           C      H       N       S      I                                        ______________________________________                                         calc. %   50.06    5.15    7.96  6.07   24.04                                  found %   49.90    4.88    7.78  6.34   23.88                                  ______________________________________                                    

EXAMPLE 23 2,beta,N-diethylaminoethylthio-4,o-chlorophenyl-3H-1,5-benzodiazepine.sup.. HCl

(Formula I wherein R = H; R¹ = o-Cl; R² = N(C₂ H₅)₂ and X = -CH₂ CH₂ -)

1 g of 50 percent sodium hydride in oil is added to a mixture of 5.74 g of 4,o-chlorophenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione (prepared in a similar way as 4,p-chlorophenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione, Example 4) in 400 ml of anhydrous benzene. After refluxing for one hour, a solution of 4.05 g of beta-diethylaminoethylchloride in 15 ml of benzene is added to the mixture and refluxed for 10 hours.

After filtering, the solvent is evaporated and the excess of beta-diethylaminoethylchloride is removed by heating for 2 hours at 60°C/0.05 mm Hg in a stream of nitrogen.

The residue is dissolved in petroleum ether, treated with charcoal and filtered. The solvent is evaporated and the residue is treated with isopropanol and weakly acidified with HCl in isopropanol. The hydrochloride is filtered and crystallized from isopropanol. Yield 5.2 g, m. p. 175°C.

    ______________________________________                                         Analysis for C.sub.21 H.sub.24 N.sub.3 SCl.HCl                                         C      H       N       Cl     S                                        ______________________________________                                         calc. %   59.71    5.97    9.95  16.79  7.59                                   found %   60.00    5.83    9.84  16.51  7.87                                   ______________________________________                                    

EXAMPLE 24 2,β,N-diethylaminoethylthio-4,o-chlorophenyl-3H-1,5-benzodiazepine iodomethylate

(Formula I wherein R = H; R¹ = o-Cl; R² = N(C₂ H₅)₂ and X = -CH₂ CH₂ -)

0.213 g of methyl iodide are added at room temperature to a solution of 0.385 g of 2,beta,N-diethylaminoethylthio-4,-o-chlorophenyl-3H-1.5-benzodiazepine in 20 ml of isopropanol. After 15 hours at 20°, the product crystallizes. It is filtered and re-crystallized from ethanol.

Yield 0.35 g, m. p. 192°-193°C.

    ______________________________________                                         Analysis for C.sub.22 H.sub.27 N.sub.3 SCl.I                                           C      H       N       S      I                                        ______________________________________                                         calc. %   50.06    5.15    7.96  6.07   24.04                                  found %   49.99    5.40    7.74  6.42   24.27                                  ______________________________________                                    

EXAMPLE 25 2,beta-N-diethylaminoethylthio-4,p-diphenylyl-3H-1,5-benzodiazepine.HCl

(Formula I wherein R = H; R¹ = p-C₆ H₅ ; R² = N(C₂ H₅)₂ and X = -CH₂ CH₂ -)

A mixture of 3.28 g of 4,p-diphenylyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione, 0.50 g of 50 percent sodium hydride in oil and 200 ml of benzene are refluxed for 30 minutes, then a solution of 2.02 g of beta-diethylaminoethyl chloride in 7 ml of benzene is added dropwise over 5 minutes. The mixture is refluxed for 10 hours. Then the mixture is cooled and the sodium chloride is filtered off. The filtrate is evaporated to dryness in vacuo at 20°-30°C. The oily residue is dissolved in petroleum ether and the insoluble product is filtered off. (1.1 g of starting product m. p. 232°C).

The filtrate is evaporated to dryness in vacuo at 20°-30°C. The residue is heated to 50° in vacuo (0.01 mm Hg) to remove the excess of beta-diethylaminoethyl chloride. This treatment is continued until the beta-diethylaminoethyl chloride disappears (TLC). The oil is then dissolved in isopropanol and weakly acidified with HCl in isopropanol.

The product crystallizes by addition of anhydrous ethyl ether to the solution.

Yield 2.8 g, m. p. 168°-169°C.

    ______________________________________                                         Analysis for C.sub.27 H.sub.29 N.sub.3 S.HCl                                           C      H       N       S                                               ______________________________________                                         calc. %   69.88    6.51    9.05  6.89                                          found %   69.36    6.66    9.19  7.10                                          ______________________________________                                    

EXAMPLE 26 2,beta,N-diethylaminoethylthio-4-diphenylyl-3H-1,5-benzodiazepine iodomethylate

(Formula I wherein R = H; R¹ = p-C₆ H₅ ; R² = N(C₂ H₅)₂ and X = -CH₂ CH₂ -)

2.13 g of methyl iodide is added to a solution of 4.27 g of 2,beta,N-diethylaminoethylthio-4-diphenylyl-3H-1,5-benzodiazepine in 60 ml of acetone. The mixture is kept at 20°-30° for 60 hours.

The crystals are filtered and recrystallized from methanol. Yield 4.75 g, m. p. 203°-204°C.

    ______________________________________                                         Analysis for C.sub.28 H.sub.32 N.sub.3 IS                                              C      H       N       I      S                                        ______________________________________                                         calc. %   59.04    5.66    7.37  22.28  5.61                                   found %   58.84    5.66    6.90  22.05  5.62                                   ______________________________________                                    

EXAMPLE 27 2,beta,N-diethylaminoethylthio-4,p-phenoxyphenyl-3H-1,5-benzodiazepine.HCl

(Formula I wherein R = H; R¹ = p-C₆ H₅ O; R² = N(C₂ H₅)₂ and X = -CH₂ CH₂ -)

A mixture of 3.44 g of 4,p-phenoxyphenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione, 0.50 g of 50 percent sodium hydride in oil and 200 ml of benzene is refluxed for 30 minutes, then a solution a 2.02 g of beta-diethylaminoethyl chloride in 7 ml of benzene is added dropwise in 5 minutes.

The mixture is refluxed for 10 hours. The mixture is then cooled and the sodium chloride is filtered off. The filtrate is evaporated to dryness in vacuo at 20°-30°C. The oily residue is dissolved in petroleum ether and the solution is filtered with charcoal.

The solvent is evaporated in vacuo and the residue is heated to 50° at 0.01 mm Hg to remove the excess of β-diethylaminoethyl chloride. This treatment is continued until the betadiethylaminoethyl chloride disappears (TLC). The oil is then dissolved in isopropanol and weakly acidified with HCl in isopropanol. The product crystallizes by addition of anhydrous ethyl ether to the solution and the crystals are collected. Yield 9.15 g, m. p. 149°C.

    ______________________________________                                         Analysis for C.sub.27 H.sub.29 N.sub.3 OS.HCl                                          C      H       N       S                                               ______________________________________                                         calc. %   67.55    6.30    8.75  6.66                                          found %   67.85    5.87    9.05  6.33                                          ______________________________________                                    

EXAMPLE 28 2,beta,N-diethylaminoethylthio-4,p-phenoxyphenyl-3H-1,5-benzodiazepine iodomethylate

(Formula I wherein R = H; R¹ = p-C₆ H₅ O; R² = N(C₂ H₅)₂ and X = -CH₂ CH₂ -)

2.13 g of methyl iodide are added to a solution of 4.43 g of 2,beta,N-diethylaminoethylthio-4,p-phenoxyphenyl-3H-1,5-benzodiazepine in 40 ml of acetone. The mixture is kept at 20°-30° for 60 hours. The crystals are filtered and recrystallized from ethanol.

Yield 4.5 g, m. p. 180°C.

    ______________________________________                                         Analysis for C.sub.28 H.sub.32 N.sub.3 OS.I                                            C      H       N       I      S                                        ______________________________________                                         calc. %   57.43    5.48    7.17  21.68  5.46                                   found %   57.15    5.50    7.37  22.38  5.64                                   ______________________________________                                    

EXAMPLE 29 2,beta-N-diethylaminoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine.HOl

(Formula I wherein R = H; R¹ = p-C₆ H₅ S-;R² = N(C₂ H₅)₂ and X = -CH₂ CH₂ -)

A mixture of 3.6 g of 4,p-phenylthiophenyl- 1,3-dihydro-2H-1,5-benzodiazepine-2-thione, 0.50 g of 50 percent sodium hydride in oil and 200 ml of benzene is refluxed for 30 minutes, then a solution of 2.02 g of beta-diethylaminoethyl chloride in 5 ml of benzene are added dropwise over 5 minutes.

The mixture is refluxed for 10 hours. The mixture is then cooled and filtered to separate the sodium chloride. The filtrate is evaporated to dryness in vacuo. The oily residue is dissolved in petroleum ether and the solution is filtered with charcoal. The solvent is evaporated in vacuo. The oily residue is heated to 50° in vacuo (0.01 mm Hg) to remove the excess of beta-diethylaminoethyl chloride. This treatment is continued until the beta-diethylaminoethyl chloride disappears (TLC). The oil is then dissolved in isopropanol and weakly acidified with HCl in propanol. The product crystallizes by addition of anhydrous ethyl ether to the solution. The crystals are filtered and recrystallized from ethyl acetate. Yield 3.65 g, m. p. 150°C.

    ______________________________________                                         Analysis for C.sub.27 H.sub.29 N.sub.3 S.sub.2.HCl                                     C      H       N       S                                               ______________________________________                                         calc. %   65.36    6.09    8.47  12.90                                         found %   65.18    6.40    8.52  12.85                                         ______________________________________                                    

EXAMPLE 30 2,beta,N-diethylaminoethylthio-4,p-phenylthio-phenyl-3H-1,5-benzodiazepine iodomethylate

(Formula I wherein R = H; R¹ = p-C₆ H₅ S-; R² = N(C₂ H₅)₂ and X = -CH₂ -CH₂ -)

2.55 g of methyl iodide are added to a solution of 5.93 g of 2,beta,N-diethylaminoethylthio-4-p-phenylthiophenyl-3H-1,5-benzodiazepine in 100 ml of isopropanol. The mixture is kept at 20°-30° for 60 hours. The crystals are then filtered. Yield 6.2 g, m. p. 161°C.

    ______________________________________                                         Analysis for C.sub.28 H.sub.32 N.sub.3 S.sub.2.I                                       C      H       N       I      S                                        ______________________________________                                         calc. %   55.90    5.36    6.98  21.10  10.64                                  found %   55.72    5.29    7.11  21.27  10.73                                  ______________________________________                                    

EXAMPLE 31 2,beta,N-diethylaminoethylthio-4,p-phenylthio-phenyl-3H-1,5-benzodiazepine bromobenzylate

(Formula I wherein R = H; R¹ - p-C₆ H₅ S-; R² = N(C₂ H₅)₂ and X = -CH₂ -CH₂ -)

0.427 g of benzyl bromide is added to a solution of 0.918 g of 2, beta,N-diethylaminoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine in 20 ml of isopropanol and the mixture is kept at 20°-25° for 4 days. It is then filtered and crystallized from isopropanol. Yield 0.8 g, m. p. 134°C.

    ______________________________________                                         Analysis for C.sub.34 H.sub.36 N.sub.3 S.sub.2 Br                                      C      H       N       S                                               ______________________________________                                         calc. %   64.74    5.75    6.66  10.17                                         found %   64.71    5.94    6.77  10.21                                         ______________________________________                                    

EXAMPLE 32 2,beta,N-diethylaminoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine methyl nitrate

(Formula I wherein R = H; R¹ = p-C₆ H₅ S-; R² = N(C₂ H₅)₂ and X = -CH₂ CH₂ -)

a. A solution of 0.601 g of 2,beta,N-diethylaminoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine iodomethylate in 6 ml of methanol is added at 25°C to a solution of 0.16 g of silver nitrate in 8.5 ml of methanol.

The precipitated silver iodide is filtered, methanol is evaporated, the residue is treated with ethyl acetate, the white solid precipitate is collected and crystallized from isopropanol. Yield 0.46 g, m. p. 149°C.

b. A 0.5 N NaOH solution is passed through a column of 10 ml of Amberlite IRA 400 resin, until the collected solution shows the same normality as the solution poured into the column. The column is then washed till the washing waters are neutral. Then, a solution of 1.2 g of 2,beta,N-diethylaminoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine iodomethylate in 80 ml of ethanol and 20 ml of water is passed in 3 hours and the eluate is collected in a flask cooled with ice. A sample of the collected solution containing the 2,beta,N-methyldiethylammoniumethylthio-4, p-phenylthiophenyl-3H-1,5-benzodiazepine hydroxide is titrated with 0.01 N HCl : 85 percent of the theoretical yield is found.

The remaining solution is then neutralized with the theoretical quantity of nitric acid, evaporated to dryness and the oily residue is treated with ethyl acetate. A white product is obtained which is crystallized from isopropanol: theoretical yield calculated on 2,beta,N-methyldiethylammoniumethylthio-4,p-phenylthiophenyl- 3H-1,5-benzodiazepine hydroxide. m p. 148°-149°C.

    ______________________________________                                         Analysis for C.sub.28 H.sub.32 N.sub.4 S.sub.2 O.sub.3                                 C      H       N                                                       ______________________________________                                         calc. %   62.66    6.01    10.44                                               found %   62.39    5.74    10.30                                               ______________________________________                                    

EXAMPLE 33 2,beta-methyldiethylammoniumethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine tartrate hydrated

(Formula I wherein R = H; R¹ = p-C₆ H₅ S-; R² = N(C₂ H₅)₂ and X = -CH₂ CH₂ -)

A 0.5 N NaOH solution is passed through a column of 10 ml of Amberlite IRA 400 resin until the collected solution shows the same normality as the solution poured into the column. The column is then washed till the washing waters are neutral. Then, a solution of 1.2 g of 2,beta-diethylaminoethylthio-4,p-phenyl-thiophenyl-3H-1,5-benzodiazepine iodomethylate in 80 ml of ethanol and 20 ml of water is passed in about 3 hours and the eluate is collected in a flask cooled with ice. A sample of the collected solution, containing the 2,beta,methyldiethylammoniumethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine hydroxide is titrated with 0.01 N HCl : 85 percent of the theoretical yield is found. The theoretical quantity of d,1-tartaric acid is then added to the eluate and the solution is kept at 20°-30°C for 24 hours. It is then evaporated to dryness and the residue is crystallized from isopropanol. Yield 0.820 g, m. p. 58-62°C.

    ______________________________________                                         Analysis for C.sub.28 H.sub.32 N.sub.3 S.sub.2.C.sub. 4 H.sub.5 O.sub.6.H.     sub. 2 O                                                                               C      H       N       S                                               ______________________________________                                         calc. %   59.88    6.11    6.53   9.94                                         found %   60.09    5.92    6.47  10.12                                         ______________________________________                                    

EXAMPLE 34 2,beta,N(N'-methyl)piperazinoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine citrate

(Formula I wherein R = H; R¹ = p-C₆ H₅ S-; ##EQU13## and X = -CH₂ CH₂ -)

A solution of 3.6 g of 4,p-phenylthiophenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione in 200 ml of anhydrous benzene is refluxed for 30 minutes with 0.5 g of a 50 percent oily suspension of sodium hydride. A solution of 2.47 g of 2(N'-methyl)-N-piperazino-1-chloroethane in 8 ml of anhydrous benzene is then added dropwise in 10 minutes and the mixture is refluxed for 10 hours. After filtration, the solvent is evaporated and the residual oil is crystallized from petroleum ether. Yield 3.5 g of 2,beta,N-(N'-methyl)piperazinoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine m. p. 85°C.

    ______________________________________                                         Analysis for C.sub.28 H.sub.30 N.sub.4 S.sub.2                                         C      H       N        S                                              ______________________________________                                         calc. %   69.12    6.22    11.51  13.18                                        found %   68.90    6.51    11.46  13.03                                        ______________________________________                                    

To a solution of 4.86 g, of 2,beta,N-(N'-methyl)piperazinoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine in 80 ml of isopropanol 1.92 g of citric acid are added and the mixture is heated until a solution is obtained. The citrate is crystallized by cooling and is then recrystallized from ethanol. Yield 5.5 g, m. p. 174°C.

    ______________________________________                                         Analysis for C.sub.28 H.sub.30 N.sub.4 S.sub.2.C.sub. 6 H.sub.8 O.sub.7                C      H       N                                                       ______________________________________                                         calc. %   60.16    5.66    8.25                                                found %   59.96    5.88    8.69                                                ______________________________________                                    

EXAMPLE 35 2,beta,N(N'-methyl)piperazinoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine monoiodomethylate

(Formula I wherein R = H; R¹ = p-C₆ H₅ S-; ##EQU14## and X = -CH₂ CH₂ -)

0.14 g of methyl iodide are added at room temperature to a solution of 0.486 g of 2,beta,N(N'-methyl)piperazinoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine in 15 ml of isopropanol. After keeping for 4 days at room temperature, the mixture is filtered. Yield 0.58 g, m. p. 185°C.

    ______________________________________                                         Analysis for C.sub.29 H.sub.33 N.sub.4 S.sub.2 J                                       C      H       N       I      S                                        ______________________________________                                         calc. %   55.41    5.29    8.91  20.19  10.20                                  found %   55.15    5.53    8.64  19.97   9.92                                  ______________________________________                                    

EXAMPLE 36 2,beta,N(N'-methyl)piperazinoethylthio-4-p-phenylthiophenyl-3H-1,5-benzodiazepine bis-iodomethylate

(Formula I wherein R = H; R¹ = p-C₆ H₅ S-; ##EQU15## and X = -CH₂ CH₂ -)

0.426 g of methyliodide is added at room temperature to a solution of 0.486 g of 2,beta,N(N'-methyl)piperazinoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine in 15 ml of acetone. After keeping for 4 days at room temperature, the mixture is cooled, filtered and crystallized from aqueous ethanol. Yield 0.5 g; m. p. 177°C.

    ______________________________________                                         Analysis for C.sub.30 H.sub.36 N.sub.4 S.sub.2 I.sub.2                                 C      H       N       I      S                                        ______________________________________                                         calc. %   46.76    4.71    7.27  32.94  8.32                                   found %   46.86    4.85    7.09  33.10  8.32                                   ______________________________________                                    

EXAMPLE 37 2,gamma,pyrrolidinopropylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine.HC

(Formula I wherein R = H; R¹ = C₆ H₅ S-;

R² = N

and X = -CH₂ CH₂ CH₂ -)

1 g of 50 percent oily suspension of sodium hydride is added to 7.2 g of 4,p-phenylthiophenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione in 400 ml of anhydrous benzene and refluxed for 30 minutes. 4.42 g of 1,N-pyrrolidino-3-chloropropane in 15 ml of benzene is then added to the mixture and refluxed for 10 hours. It is filtered and the solvent is evaporated. The residue is heated for 2 hours at 60°C/0.2 mm Hg in a stream of nitrogen to remove the traces of 1,N-pyrrolidino-3-chloropropane. The oily residue is dissolved in petroleum ether and filtered with charcoal; the solvent is evaporated again and the residue is treated with isopropanol, and slightly acidified with HCl in isopropyl alcohol. The hydrochloride is separated by addition of ethyl ether and is crystallized from isopropanol. Yield 5.6 g; m. p. 176°C.

    ______________________________________                                         Analysis for C.sub.28 H.sub.29 N.sub.3 S.sub.2.HCl                                     C      H       N       Cl    S                                         ______________________________________                                         calc. %   66.19    5.95    8.27  6.98  12.61                                   found %   65.92    6.00    8.15  7.33  12.51                                   ______________________________________                                    

EXAMPLE 38 2,gamma,N-pyrrolidinopropylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine iodomethylate

(Formula I wherein R = H; R¹ = p-C₆ H₅ S-;

R² = N

and X = -CH₂ CH₂ CH₂ -)

0.213 g of methyl iodide is added to 0.471 g of 2,gamma,N-pyrrolidinopropylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine in 10 ml of isopropanol and the mixture is kept for 15 hours at room temperature. At the end, an oil separates and the product crystallizes from the decanted solvent. The oil treated with isopropanol solidifies and is filtered. The combined products are crystallized from ethanol. Yield 0.32 g; m. p. 190-191°C.

    ______________________________________                                         Analysis for C.sub.29 H.sub.32 N.sub.3 S.sub.2 I                                       C      H       N       S      I                                        ______________________________________                                         calc. %   56.76    5.25    6.85  10.45  20.68                                  found %   56.90    5.14    6.72  10.25  20.43                                  ______________________________________                                    

EXAMPLE 39 2,gamma,N-diethylaminopropylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine citrate

(Formula I wherein R = H; R¹ = p-C₆ H₅ S-; R² = N(C₂ H₅)₂ and X = -CH₂ CH₂ CH₂ -)

0.5 g of a 50 percent sodium hydride suspension in oil are added to a solution of 3.6 g of 4,p-phenylthiophenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione in 200 ml of benzene, and refluxed for 30 minutes. The mixture is refluxed with 2.02 g of 1-chloro-3-diethylaminopropane for 10 hours. The solvent is evaporated, and the residue is heated for 2 hours at 65°C/0.2 mm Hg. The residue is purified again by countercurrent repartition using n-butanol-water. The separation is controlled by TLC on silica gel using as a solvent butanol saturated with water and acetic acid and revealing the spots with K iodobismuthate. The fractions containing the pure product are evaporated in vacuo. To solution of this residue in 120 ml of isopropanol, 1.92 g of citric acid is added and refluxed for 10 minutes. After cooling, an oil is separated which is crystallized from ethyl acetate. A further quantity of product is separated from isopropanol solution by further cooling, crystallized from ethyl acetate and combined to the first portion. Total yield 4.3 g, m. p. 114°-115°C.

    ______________________________________                                         Analysis for C.sub.28 H.sub.31 N.sub.3 S.sub.2.C.sub. 6 H.sub.8 O.sub.7                C      H       N       S                                               ______________________________________                                         calc. %   61.33    5.90    6.31  9.63                                          found %   61.05    5.55    6.27  9.78                                          ______________________________________                                    

EXAMPLE 40 2,gamma,N-diethylaminopropylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine iodomethylate

(Formula I wherein R = H; R¹ = p-C₆ H₅ S-; R² = N(C₂ H₅)₂ and X = -CH₂ CH₂ CH₂ -)

A solution of 2.4 g of 2,gamma,N-diethylaminopropylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine in 80 ml of acetone and 1.06 g of methyl iodide is kept four days at 2°-25°C. After cooling, the mixture is filtered. Yield 2.15 g, m. p. 174°C. The substance crystallizes from anhydrous ethanol.

    ______________________________________                                         Analysis for C.sub.29 H.sub.34 N.sub.3 S.sub.2 I                                       C      H       N       S      I                                        ______________________________________                                         calc. %   56.58    5.57    6.83  10.42  20.62                                  found %   56.73    5.95    6.80  10.65  20.89                                  ______________________________________                                    

EXAMPLE 41 2,gamma,N-dimethylaminopropylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine.HCl

(Formula I wherein R = H; R¹ = p-C₆ H₅ S-; R² = N(CH₃)₂ and X = -CH₂ CH₂ CH₂ -)

A solution of 3.6 g of 4,p-phenylthiophenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione in 200 ml of anhydrous benzene is refluxed for 30 minutes with 0.5 g of a 50 percent sodium hydride oily suspension. A solution of 1.824 g of gamma-dimethylaminopropyl chloride in 7 ml of benzene is then added and the mixture is refluxed for 10 hours. The hot solution is filtered, the solvent is evaporated and the residual oil is heated for 2 hours at 65°C/0.2 mm Hg to remove the excess of gamma-dimethylaminopropyl chloride. The residue is extracted with petroleum ether, removing the less soluble product. The solvent is evaporated, the residue is treated with isopropyl alcohol and the solution slightly acidified with HCl in isopropanol. The hydrochloride is separated by addition of ethyl ether and crystallized from isopropanol. Yield 2.75 g, m. p. 111°-112°C.

    ______________________________________                                         Analysis for C.sub.26 H.sub.27 N.sub.3 S.sub.2.HCl                                     C      H       N       Cl    S                                         ______________________________________                                         calc. %   64.77    5.85    8.72  7.35  13.30                                   found %   64.43    6.11    8.56  7.43  13.11                                   ______________________________________                                    

EXAMPLE 42 2,gamma,N-dimethylaminopropylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine iodomethylate

(Formula I wherein R = H; R¹ = p-C₆ H₅ S-; R² = N(CH₃)₂ and X = -CH₂ CH₂ CH₂ -)

A solution of 2.34 g of 2,gamma,N-dimethylaminopropylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine in 20 ml of acetone and 1.06 g of methyl iodide is kept for 4 days at 20°-25°C. The mixture is cooled, the separated crystals are filtered and recrystallized from ethanol. Yield 2.59 g, m. p. 200°C.

    ______________________________________                                         Analysis for C.sub.27 H.sub.30 N.sub.3 S.sub.2 I                                       C      H       N       S      I                                        ______________________________________                                         calc. %   55.19    5.15    7.15  10.91  21.60                                  found %   54.81    5.33    6.93  10.74  22.00                                  ______________________________________                                    

EXAMPLE 43 2,beta,N-pyrrolidinoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine

(Formula I wherein R = H; R¹ =- p-C₆ H₅ S-;

R² = N

and X = -CH₂ CH₂ -)

0.5 g of a 50 percent sodium hydride oily suspension is added to a solution of 3.6 g of 4,p-phenylthiophenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione in 200 ml of anhydrous benzene and refluxed for 30 minutes. To this mixture, a solution of 2 g of beta-pyrrolidinoethyl chloride in 7 ml of benzene is added, refluxed for 10 hours and filtered. The solvent is evaporated and the excess of beta-pyrrolidinoethyl chloride is removed by heating for 2 hours at 60°C/1 mm Hg. The residual oil is crystallized from petroleum ether and filtered. Yield 3.4 g, m. p. 82°C.

    ______________________________________                                         Analysis for C.sub.27 H.sub.27 N.sub.3 S.sub.2                                         C      H       N                                                       ______________________________________                                         calc. %   70.86    5.95    9.18                                                found %   70.56    6.04    9.31                                                ______________________________________                                    

EXAMPLE 44 2, beta,N-pyrrolidinoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine iodomethylate

(Formula I wherein R = H; R¹ = p-C₆ H₅ S-;

R² = N

and X = -CH₂ CH₂ -)

A solution of 2.3 g of 2,beta,N-pyrrolidinoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine in 12 ml of acetone and 1.06 g of methyl iodide is kept for four days at 20°-25°C. After cooling, the mixture is filtered and crystallized from 95 percent ethanol. Yield 2.2 g, m. p. 191°C.

    ______________________________________                                         Analysis for C.sub.28 H.sub.30 N.sub.3 S.sub.2 I                                       C      H       N       S      I                                        ______________________________________                                         calc. %   56.08    5.04    7.01  10.70  21.17                                  found %   56.15    5.15    6.76  10.47  21.49                                  ______________________________________                                    

EXAMPLE 45 2,beta,N-dimethylaminoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine citrate

(Formula I wherein R = H; R¹ = P-C₆ H₅ S-; R² = N(CH₃)₂ and X = -CH₂ CH₂ -)

0.5 g of a 50 percent sodium hydride oily suspension are added to a solution of 3.6 g of 4,p-phenylthiophenyl-1,3-dihydro-2H-1,5-bensodiazepine-2-thione in 200 ml of anhydrous benzene and refluxed for 30 minutes. A solution of 1.61 g of beta-dimethyl-aminoethyl chloride in 7 ml of benzene is added, the mixture is refluxed for 10 hours and filtered. The solvent is evaporated, and the excess of beta-dimethylaminoethyl chloride is removed by heating for 2 hours at 65°C/0.2 mm Hg. The residual oil is extracted with cold petroleum ether, removing the less soluble product. The solvent is evaporated and to a solution of the residue in 240 ml of hot isopropanol, 1.92 g of citric acid are added. After one night at room temperature, the mixture is cooled and filtered and then crystallized from isopropanol. Yield 3.66 g, m. p. 78°C.

    ______________________________________                                         Analysis for C.sub.25 H.sub.25 N.sub.3 S.sub.2.C.sub. 6 H.sub.8 O.sub.7                C      H       N       S                                               ______________________________________                                         calc. %   59.69    5.33    6.74  10.38                                         found %   59.63    5.63    6.46  10.09                                         ______________________________________                                    

EXAMPLE 46 2,beta,N-dimethylaminoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine iodomethylate

(Formula I wherein R = H; R¹ = p-C₆ H₅ S; R² = N(CH₃)₂ and X = -CH₂ CH₂ -)

1.06 g of methyl iodide is added to a solution of 2.16 g of 2,beta,N-dimethylaminoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine in 80 ml of isopropanol and kept for 4 days at 20°-25°C. After cooling, the mixture is filtered. Yield 2.3 g, m. p. 200°C. The substance crystallizes from ethanol.

    ______________________________________                                         Analysis for C.sub.26 H.sub.28 N.sub.3 S.sub.2 I                                       C      H       N       S      I                                        ______________________________________                                         calc. %   54.45    4.92    7.33  11.18  22.13                                  found %   54.34    5.06    7.31  11.31  22.48                                  ______________________________________                                    

EXAMPLE 47 2,beta,N-piperidinoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine

(Formula I wherein R = H; R¹ = p-C₆ H₅ S-;

R² = N

and X = -CH₂ CH₂ -)

A solution of 3.6 g of 4,p-phenylthiophenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione in 200 ml of anhydrous benzene and 0.5 g of a 50 percent sodium hydride oily suspension is refluxed for 30 minutes. To this mixture a solution of 2.015 g of beta,N-piperidinoethylchloride in 7 ml of benzene is added, refluxed for 10 hours and filtered. The solvent is evaporated and the residual oil is heated for 2 hours at 65°C/0.2 mm Hg to remove the excess of beta,N-piperidinoethyl chloride. The residue is crystallized from ligroine. Yield 3.4 g, m. p. 78°C.

    ______________________________________                                         Analysis for C.sub.28 H.sub.29 N.sub.3 S.sub.2                                         C      H       N       S                                               ______________________________________                                         calc. %   71.29    6.20    8.91  13.60                                         found %   71.45    6.34    8.91  13.80                                         ______________________________________                                    

The hydrochloride is prepared by slightly acidifying with HCl an isopropanol solution of the base. The substance crystallizes from isopropyl alcohol; m. p. 144°-145°C.

    ______________________________________                                         Analysis for C.sub.28 H.sub.29 N.sub.3 S.sub.2.HCl.H.sub. 2 O                  C           H       N       Cl    S      H.sub.2 O                             ______________________________________                                         calc. %                                                                               63.92    6.13    7.99  6.74  12.19  3.42                                found %                                                                               64.09    6.60    7.76  6.74  11.98  3.33                                ______________________________________                                    

EXAMPLE 48 2,beta,N-piperidinoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine iodomethylate

(Formula I wherein R = H; R¹ = p-C₆ H₅ S-;

R² = N

and X = -CH₂ CH₂ -)

3.5 g of methyl iodide are added to a solution of 1.97 g of 2,beta-N-piperidinoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine in 64 ml of acetone and the solution is kept for 4 days at 20°-25°C. After cooling, the mixture is filtered.

Yield 1.9 g, m. p. 180°C. The substance crystallizes from ethanol.

    ______________________________________                                         Analysis for C.sub.29 H.sub.32 N.sub.3 S.sub.2 I                                       C      H       N       S      I                                        ______________________________________                                         calc. %   56.71    5.25    6.84  10.44  20.66                                  found %   56.82    5.51    6.78  10.14  21.02                                  ______________________________________                                    

EXAMPLE 49 2,beta,N-morpholinoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine.HCl

(Formula I wherein R = H; R¹ = p-C₆ H₅ S-; ##EQU16## and X = -CH₂ CH₂ -)

A solution of 3.6 g of 4,p-phenylthiophenyl-1,3-dihydro-2H-1,5-benzodiazepine -2-thione in 200 ml of anhydrous ether and 0.5 g of sodium hydride is refluxed for 30 minutes. A solution of 2.245 g of beta,N-morpholinoethyl chloride in 7 ml of ethyl ether is added and refluxed for 10 hours. The hot solution is filtered, and the solvent is evaporated, and the traces of beta,N-morpholinoethyl chloride are removed by heating for 2 hours at 65°C/0.2 mm Hg. The residue is dissolved in 160 ml isopropanol and slightly acidified with HCl in isopropanol. The precipitate is crystallized from isopropyl alcohol. Yield 3.7 g, m. p. 215°C.

    ______________________________________                                         Analysis for C.sub.27 H.sub.27 N.sub.3 OS.sub.2.HCl                                    C      H       N       Cl     S                                        ______________________________________                                         calc. %   63.57    5.53    8.23  6.95   12.57                                  found %   63.77    5.77    8.26  7.30   12.24                                  ______________________________________                                    

EXAMPLE 50 2,beta,N-morpholinoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine iodomethylate

(Formula I wherein R = H; R¹ = p-C₆ H₅ S-: ##EQU17## and X = -CH₂ CH₂ -)

A solution of 2.36 g of 2,beta,N-morpholino-ethylthio-4,-p-phenylthiophenyl-3H-1,5-benzodiazepine in 120 ml of acetone and 1.06 g of methyl iodide is kept at 20°-25°C for four days. After cooling, the mixture is filtered.

Yield 2.52 g, m. p. 173°C. The substance crystallizes from ethanol.

    ______________________________________                                         Analysis for C.sub.28 H.sub.30 N.sub.3 S.sub.2 OI                                      C      H       N       S      I                                        ______________________________________                                         calc. %   54.63    4.91    6.83  10.42  20.62                                  found %   54.48    5.08    6.44  10.38  21.07                                  ______________________________________                                    

EXAMPLE 51 2(alpha-methyl-beta-diethylamino)ethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine citrate

(Formula I wherein R = H; R¹ = p-C₆ H₅ S-; R² = N(C₂ H₅)₂ and ##EQU18##

1 g of NaH in a 50 percent oily suspension is added to a solution of 7.2 g of 4,p-phenylthiophenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione in 400 ml of anhydrous benzene and refluxed for 30 minutes. To the mixture 4.5 g of 1-diethylamino-2-chloropropane is added, refluxed for 10 hours and filtered. The solvent is evaporated and the residue is heated for 2 hours at 60°C/0.2 mm Hg in a stream of nitrogen to remove the traces of 1-diethylamino-2-chloropropane. The residue is dissolved in petroleum ether and filtered with charcoal; the solvent is evaporated, the residue is dissolved in hot isopropanol and 3.84 g of citric acid are added to the solution. After one night at room temperature, an oil is separated, the liquid is decanted, evaporated to dryness, and crystallized from ethyl acetate. The oil is dissolved and crystallized from ethyl acetate. The products are collected together and recrystallized from ethyl acetate. Yield 7 g, m. p. 138° C.

    ______________________________________                                         Analysis for C.sub.28 H.sub.31 N.sub.3 S.sub.2.C.sub. 6 H.sub.8 O.sub.7                C      H       N       S                                               ______________________________________                                         calc. %   61.33    5.90    6.31  9.48                                          found %   61.01    5.99    6.19  9.69                                          ______________________________________                                    

The chemical and physical data of other products having the general formula I and of their salts of addition with the acids, inclusive of the quaternary ammonium salts, prepared by the methods according to the invention, are reported in Table I. The chemical and physical data of the intermediate products having the formulae II and III, respectively, are reported in Tables II and III. ##SPC2##

                                      TABLE I                                      __________________________________________________________________________     Compound                               Crystallization                                                                          Melting point                 No.  R     R.sup.1     R.sup.2 X       solvent   °C                     __________________________________________________________________________     52   H     H           N(CH.sub.3).sub.2                                                                      CH.sub.2 CH.sub.2                                                                      methyl alcohol  182                     53   "     "           N(C.sub.2 H.sub.5).sub.2                                                               "       isopropyl alcohol                                                                              152                     54   "     "           "       "       ethyl alcohol   180                     55   "     "           "       CH.sub.2 CH.sub.2 CH.sub.2                                                             ethyl alcohol-ethyl                                                                            85her                   56   "     "           "       "       dimethyl ketone 158                     57   "     "           N       CH.sub.2 CH.sub.2                                                                      isopropyl alcohol-ethyl                                                                        192-193                 58   "     "           "       "       dimethyl ketone 177-178                 59   "     "           N       "       isopropyl alcohol-ethyl                                                                        181er                   60   H     H           N       CH.sub.2 CH.sub.2                                                                      isopropyl alcohol                                                                              186                     61   "     "           N       "       isopropyl alcohol-ethyl                                                                        208er                   62   "     "           "       "       methyl alcohol  177                     63   "     "           NN--CH.sub.3                                                                           "         "  "          172                     64   "     "           "       "       methyl alcohol-ethyl                                                                           121-122                 65   "     "           "       "       methyl alcohol  170                     66   "     4--CH.sub.3 N(C.sub.2 H.sub.5).sub.2                                                               "       petroleum ether 59-60                   67   "     "           "       "       ethyl acetate   157                     68   "     "           "       "       ethyl alcohol   183                     69   "     4--CH.sub.3 O                                                                              "       "       isopropyl alcohol-ethyl                                                                        167er                   70   "     "           "       ethyl alcohol                                                                          183                                     71   H     4--Br       N(C.sub.2 H.sub.5).sub.2                                                               CH.sub.2 CH.sub.2                                                                      ethyl acetate   154                     72   "     "           "       "       ethyl alcohol   185                     73   "     4--CH.sub.3 S                                                                              "       "       ethyl acetate   164                     74   "     "           "       "       methyl alcohol  195                     75   "     4--C.sub.2 H.sub.5 S                                                                       "       "       ethyl acetate   113                     76   "     "           "       "       ethyl alcohol   192                     77   "     4--nC.sub.3 H.sub.7 S                                                                      "       "       ethyl acetate   136                     78   "     "           "       "       ethyl alcohol   186                     79   "     4--iC.sub.3 H.sub.7 S                                                                      "       "       ethyl acetate   116                     80   "     "           "       "       ethyl alcohol   199-200                 81   "     4--nC.sub.4 H.sub.9 S                                                                      "       "       isopropyl alcohol                                                                              42                      82   "     "           "       "       ethyl alcohol   177                     83   "     4--CH.sub.3 --CHCH.sub.2 CH.sub.2 S                                                        "       "       ethyl acetate   100                          |                                                                     CH.sub.3                                                                  84   H     4--CH.sub.3 --CHCH.sub.2 CH.sub.2 S                                                        N(C.sub.2 H.sub.5).sub.2                                                               CH.sub.2 CH.sub.2                                                                      ethyl alcohol   172                                |                                                                     CH.sub.3                                                            85   "     4--nC.sub.12 H.sub.25 S                                                                    "       "       ethyl alcohol   117                     86   "     "           "       "       ethyl alcohol   142                     87   2--CH.sub.3 O                                                                        4--CH.sub.3 O                                                                              "       "       petroleum ether 81-82                   88   "     "           "       "       ethyl alcohol   167                     89   2--Cl 4-- Cl      "       "       ethyl alcohol   188                     90   "     "           "       "       ethyl alcohol   176                     91   3--Cl "           "       "       ethyl acetate   169                     92   3--Cl "           "       "       ethyl alcohol   186                     93   H     2--C.sub.6 H.sub.5 S                                                                       "       "       isopropyl alcohol                                                                              183                     94   "     "           "       "       ethyl alcohol   197                     95   "     4--S        "       "       ethyl alcohol   172                     96   "     "           "       "       ethyl alcohol   188                     97   "     4--C.sub.6 H.sub.5 CH.sub.2 S                                                              "       "       isopropyl alcohol                                                                              141                     __________________________________________________________________________     Compound                                Crystallization                        No.         X       R.sub.1   R.sub.1                                                                            R.sub.2                                                                               solvent   M.P.                        __________________________________________________________________________      98        CH.sub.2 CH.sub.2                                                                      4 Cl       H  N(C.sub.2 H.sub.5).sub.2                                                              isopropyl alcohol                                                                         168                          99        CH.sub.2 CH.sub.2 CH.sub.2                                                             4 Cl       H  N(C.sub.2 H.sub.5).sub.2                                                              isopropyl alcohol                                                                         139-140                     100        CH.sub.2 CH.sub.2                                                                      3 Cl       H  N(C.sub.2 H.sub.5).sub.2                                                              isopropyl alcohol                                                                         142                         101        CH.sub.2 CH.sub.2                                                                      2 Cl       H  N(C.sub.2 H.sub.5).sub.2                                                              isopropyl alcohol                                                                         170                         102        CH.sub.2 CH.sub.2                                                                      4--        H  N(C.sub.2 H.sub.5).sub.2                                                              isopropyl alcohol                                                                         189                         103        CH.sub.2 CH.sub.2                                                                      4O         H  N(C.sub.2 H.sub.5).sub.2                                                              isopropyl alcohol                                                                         159                         104        CH.sub.2 CH.sub.2 CH.sub.2                                                             4S         H  N      isopropyl alcohol                                                                         173-174                     105        CH.sub.2 CH.sub.2 CH.sub.2                                                             4S         H  N(C.sub.2 H.sub.5).sub.2                                                              isopropyl alcohol                                                                         149-150                     106        CH.sub.2 CH.sub.2 CH.sub.2                                                             4S         H  N(CH.sub.3).sub.2                                                                     isopropyl alcohol                                                                         172                         107        CH.sub.2 CH.sub.2                                                                      4S         H  N      isopropyl alcohol                                                                         170                         108        CH.sub.2 CH.sub.2                                                                      4S         H  N(CH.sub.3).sub.2                                                                     isopropyl alcohol                                                                         173                         109        CH.sub.2 CH.sub.2                                                                      4S         H  N      isopropyl alcohol                                                                         166                         110        CH.sub.2 CH.sub.2                                                                      4S         H  NO     isopropyl alcohol                                                                         149                         111        CH.sub.2 CH.sub.2                                                                        H        H  N      isopropyl alcohol                                                                         145                         112        CH.sub.2 CH.sub.2                                                                        H        H  NO     ethyl alcohol                                                                             172-173                     113        CH.sub.2 CH.sub.2                                                                      4,methylthio                                                                              H  N(C.sub.2 H.sub.5).sub.2                                                              isopropyl alcohol                                                                         172                         114        CH.sub.2 CH.sub.2                                                                      4,--N--butylthio                                                                          H  N(C.sub.2 H.sub.5).sub.2                                                              isopropyl alcohol                                                                         158                         115        CH.sub.2 CH.sub.2                                                                      4,N propylthio                                                                            H  N(C.sub.2 H.sub.5).sub.2                                                              isopropyl alcohol                                                                         157                         116        CH.sub.2 CH.sub.2                                                                        4--Br    H  N(C.sub.2 H.sub.5).sub.2                                                              isopropyl alcohol                                                                         163                         117        CH.sub.2 CH.sub.2                                                                      4,ethylthio                                                                               H  N(C.sub.2 H.sub.5).sub.2                                                              isopropyl alcohol                                                                         157                         118        CH.sub.2 CH.sub.2                                                                      4,isopropylthio                                                                           H  N(C.sub.2 H.sub.5).sub.2                                                              isopropyl alcohol                                                                         174                         __________________________________________________________________________                     Calculated              Found                                  Compound                         I                       I                     No.   Formula   C   H  N    S    (+ Cl) C   H  N    S    (+ Cl)                                                 (++H.sub.2 O)           (++H.sub.2            __________________________________________________________________________                                                              O)                    52   C.sub.19 H.sub.21 N.sub.3 S.CH.sub. 3 I                                                   51.61                                                                              5.19                                                                              9.03 6.89 27.25  51.93                                                                              4.91                                                                              9.40 6.93 27.64                 53   C.sub.21 H.sub.25 N.sub.3 S.HCl                                                           HCl 65.01                                                                             6.75 10.83                                                                               8.24       64.96                                                                             7.01 10.76                                                                               8.42                  54   C.sub.21 H.sub.25 N.sub.3 S.CH.sub. 3 I                                                   53.54                                                                              5.72                                                                              8.39 6.48 25.72  53.58                                                                              5.68                                                                              8.43 6.52 25.80                 55   C.sub.22 H.sub.27 N.sub.3 S.HCl.HCl.H.sub.. 2O                                            62.91                                                                              7.20                                                                              10.00                                                                               7.62 4.28++ 62.48                                                                              6.90                                                                              10.30                                                                               7.70 4.30++                56 C.sub.22 H.sub.27 N.sub.3 S.CH.sub. 3 I                                          54.43      5.95                                                                               8.28                                                                              6.30 25.01                                                                               54.22  6.02                                                                               8.19                                                                              6.61 24.95                      57   C.sub.21 H.sub.23 N.sub.3 S.HCl                                                           65.35                                                                              6.26                                                                              10.89                                                                               8.29        65.15                                                                              6.61                                                                              11.09                                                                               8.44                       58   C.sub.21 H.sub.23 N.sub.3 S.CH.sub. 3 I                                                   53.76                                                                              5.33                                                                              8.55 6.51 25.83  53.82                                                                              5.67                                                                              8.47 6.57 25.62                 59   C.sub.22 H.sub.25 N.sub.3 S.sup.. HCl                                                     66.08                                                                              6.55                                                                              10.51                                                                               8.00        66.19                                                                              6.87                                                                              10.72                                                                               8.08                       60   C.sub.22 H.sub.25 N.sub.3 S.sup.. CH.sub.3 I                                              54.65                                                                              5.58                                                                              8.31 6.31 25.11  54.27                                                                              5.71                                                                              8.21 6.18 25.62                 61   C.sub.21 H.sub.23 N.sub. 3 OS.HCl                                                         62.75                                                                              6.01                                                                              10.46                                                                               7.96        62.59                                                                              6.06                                                                              10.67                                                                               8.29                       62   C.sub.21 H.sub.32 N.sub.3 OS.CH.sub. 3 I                                                  52.07                                                                              5.16                                                                              8.28 6.30 25.01  51.79                                                                              5.08                                                                              8.10 6.73 25.11                 63   C.sub.22 H.sub.26 N.sub.4 S.HCl                                                           58.53                                                                              6.25                                                                              12.41                                                                               7.08        58.18                                                                              6.40                                                                              12.37                                                                               7.24                       64   C.sub.22 H.sub.26 N.sub.4 S.sup.. CH.sub.3 I                                              53.07                                                                              5.61                                                                              10.77                                                                               6.14 24.39  52.73                                                                              5.58                                                                              10.49                                                                               6.29 23.95                 65   C.sub.22 H.sub.26 N.sub.4 S.2CH.sub. 3 I                                                  43.51                                                                              4.87                                                                              8.45 4.83 38.42  43.65                                                                              5.19                                                                              8.54 5.15 38.33                 66   C.sub.22 H.sub.27 N.sub.3 S                                                               72.30                                                                              7.18    8.76        72.47                                                                              7.45    8.86                       67   C.sub.2 H.sub.27 N.sub.3 S.HCl                                                            65.74                                                                              7.02                                                                              10.45                                                                               7.96 8.82+  66.19                                                                              7.17                                                                              10.58     8.85+                 68   C.sub.22 H.sub.27 N.sub.3 S.CH.sub. 3 I                                                   54.43                                                                              6.06                                                                              8.28 6.30 25.01  54.45                                                                              5.74                                                                              8.22 6.41 25.61                 69   C.sub.22 H.sub.27 N.sub.3 OS.HCl                                                          63.21                                                                              6.75                                                                              10.05                                                                               7.65        62.87                                                                              6.81                                                                              9.95 7.64                       70   C.sub.22 H.sub.27 N.sub.3 OS.CH.sub. 3 I                                                  52.77                                                                              5.77                                                                              8.02 6.11 24.25  52.58                                                                              5.39                                                                              7.97 6.24 24.36                 71   C.sub.21 H.sub.24 BrN.sub.3 S.HCl                                                         54.03                                                                              5.40                                                                              9.00 6.87 7.59+  54.05                                                                              5.20                                                                              9.28 7.18 7.92+                 72   C.sub.21 H.sub.24 BrN.sub.3 S.CH.sub. 3 I                                                 46.17                                                                              4.75                                                                              7.34 5.60        46.18                                                                              4.49                                                                              7.57 5.53                       73   C.sub.22 H.sub.27 N.sub.3 S.sub.2.HCl                                                     60.88                                                                              6.50                                                                              9.68 14.77                                                                               8.17+  61.02                                                                              6.75                                                                              9.63 14.68                                                                               8.33+                 74   C.sub.22 H.sub.27 N.sub.2 S.sub.2.CH.sub. 3 I                                             51.20                                                                              5.60                                                                              7.79 11.89                                                                               23.52  51.08                                                                              5.33                                                                              8.15 11.93                                                                               23.57                 75   C.sub.22 H.sub.29 N.sub.3 S.sub.2.CH.sub.6 H.sub.8 O.sub.                                 57.70                                                                              6.18                                                                              6.96 10.62       57.76                                                                              6.40                                                                              6.64 10.72                      76   C.sub.23 H.sub.29 N.sub.3 S.sub.2.CH.sub. 3 I                                             52.07                                                                              5.83                                                                              7.59 11.58                                                                               22.92  52.04                                                                              5.82                                                                              7.78 11.44                                                                               23.08                 77   C.sub.24 H.sub.31 N.sub.3 S.sub.2.HCl                                                     62.28                                                                              6.98                                                                              9.09 13.88                                                                               7.67+  62.50                                                                              6.92                                                                              9.32 13.91                                                                               7.99+                 78   C.sub.24 H.sub.31 N.sub.3 S.sub.2.CH.sub. 3 I                                             52.90                                                                              6.04                                                                              7.40 11.30                                                                               22.36  52.55                                                                              5.82                                                                              7.61 11.56                                                                               22.62                 79   C.sub.24 H.sub.31 N.sub.3 S.sub.2.C.sub. 6 H.sub.8 O.sub.7                                58.32                                                                              6.36                                                                              6.80 10.38       58.08                                                                              6.46                                                                              6.51 10.06                      80   C.sub.24 N.sub.31 N.sub.3 S.sub.2.CH.sub. 3 I                                             52.90                                                                              6.04                                                                              7.40 11.30                                                                               22.36  52.48                                                                              5.96                                                                              7.11 11.59                                                                               22.89                 81   C.sub.25 H.sub.33 N.sub.3 S.sub.2                                                         68.29                                                                              7.56                                                                              9.56 14.58       68.47                                                                              7.95                                                                              9.38 14.60                      82   C.sub.25 H.sub.33 N.sub.3 S.sub.2.CH.sub. 3 I                                             53.70                                                                              6.24                                                                              7.22 11.03                                                                               21.82  53.92                                                                              6.42                                                                              6.91 11.34                                                                               22.02                 83   C.sub.26 H.sub.25 N.sub.3 S.sub.2.C.sub.6 H.sub.8 O.sub.                                  59.52                                                                              6.71                                                                              6.51 9.93        59.45                                                                              6.26                                                                              6.29 9.88                       84   C.sub.26 H.sub.35 N.sub.3 S.sub.2.CH.sub. 3 I                                             54.43                                                                              6.43                                                                              7.05 10.86                                                                               21.30  54.21                                                                              6.46                                                                              6.90 10.70                                                                               21.54                 85   C.sub.33 H.sub.49 N.sub.3 S.sub.2.C.sub.6 H.sub.8 O.sub.                                  62.96                                                                              7.72                                                                              5.65 8.62        62.56                                                                              8.06                                                                              5.67 8.98                       86   C.sub.33 H.sub.49 N.sub.3 S.sub.2.CH.sub.3 I                                              58.86                                                                              7.55                                                                              6.06 9.24 18.29  58.73                                                                              7.44                                                                              6.00 9.54 18.36                 87   C.sub.23 H.sub.29 N.sub.3 O.sub.2 S                                                       67.12                                                                              7.12                                                                              10.21                                                                               7.79        67.40                                                                              7.39                                                                              10.23                                                                               7.95                       88   C.sub.23 H.sub.29 N.sub.3 O.sub.2 S.CH.sub. 3 I                                           52.08                                                                              5.83                                                                              7.59 5.79 22.93  52.22                                                                              5.84                                                                              7.34 5.96 23.19                 89   C.sub.21 H.sub.23 Cl.sub.2 N.sub.3 S.HCl                                                  55.21                                                                              5.29                                                                              9.20 7.02 23.28+ 54.82                                                                              5.13                                                                              9.00 7.31 22.94+                90   C.sub.21 H.sub.23 Cl.sub.2 N.sub.3 S.CH.sub. 3 I                                          46.99                                                                              4.66                                                                              7.47 5.70 22.57  46.74                                                                              4.48                                                                              7.25 5.87 22.36                 91   C.sub.21 H.sub.23 Cl.sub.2 N.sub.3 S.HCl                                                  55.21                                                                              5.29                                                                              9.20 7.02 23.28+ 54.96                                                                              4.85                                                                              9.10 7.17 23.19+                92   C.sub.21 H.sub.23 Cl.sub.2 N.sub.3 S.CH.sub. 3 I                                          46.99                                                                              4.66                                                                              7.47 5.70 22.57  46.70                                                                              4.60                                                                              7.17 6.09 22.80                 93   C.sub.27 H.sub.29 N.sub.3 S.sub.2.HCl                                                     66.36                                                                              6.09                                                                              8.47 12.92                                                                               7.15+  65.16                                                                              5.72                                                                              8.30 13.02                                                                               7.39                  94   C.sub.27 H.sub.29 N.sub.3 S.sub.2.CH.sub. 3 J                                             55.90                                                                              5.34                                                                              6.98 10.66                                                                               21.09  56.00                                                                              5.24                                                                              6.82 10.54                                                                               20.90                 95   C.sub.27 H.sub.35 N.sub.3 S.sub.2.HCl                                                     64.58                                                                              7.23                                                                              8.37 12.77                                                                               7.06+  64.34                                                                              7.21                                                                              8.07 12.53                                                                               7.19+                 96   C.sub.27 N.sub.35 N.sub.3 S.sub.2.CH.sub. 3 J                                             55.35                                                                              6.30                                                                              6.92 10.55                                                                               20.88  55.40                                                                              6.34                                                                              6.76 10.43                                                                               21.25                 97   C.sub.28 H.sub.31 N.sub.3 S.sub.2.HCl                                                     65.92                                                                              6.32                                                                              8.24 12.57                                                                               6.95+  65.74                                                                              6.31                                                                              7.92 12.52                                                                               7.17+                 __________________________________________________________________________                            Calculated       Found                                  Compound                                                                       No.           Formula  C     H    N     C     H    N                           __________________________________________________________________________     11 98        C.sub.22 H.sub.27 C1n.sub.4 O.sub.3 S                                                    57.07 5.88 12.10 56.93 5.82 12.00                        99          C.sub.23 H.sub.29 C1N.sub.4 O.sub.3 S                                                    57.91 6.13 11.74 57.84 6.39 11.56                       100          C.sub.22 H.sub.27 C1N.sub.4 O.sub.3 S                                                    57.07 5.88 12.10 56.81 5.59 11.97                       101          C.sub.22 H.sub.27 C1N.sub.4 O.sub.3 S                                                    57.07 5.88 12.10 56.86 5.91 11.93                       102          C.sub.28 H.sub.32 N.sub.4 O.sub.3 S                                                      66.64 6.39 11.10 66.48 6.60 11.09                       103          C.sub.28 H.sub.32 N.sub.4 O.sub.4 S                                                      64.60 6.19 10.86 64.32 6.45 10.65                       104          C.sub.29 H.sub.32 N.sub.4 O.sub.3 S.sub.2                                                63.48 5.88 10.21 63.24 5.92 10.07                       105          C.sub.29 H.sub.34 N.sub.4 O.sub.3 S.sub.2                                                63.25 6.23 10.17 63.31 6.23 9.90                        106          C.sub.27 H.sub.30 N.sub.4 O.sub.3 S.sub.2                                                62.05 5.78 10.82 61.88 6.22 10.60                       107          C.sub.28 H.sub.30 N.sub.4 O.sub.3 S.sub.2                                                62.90 5.65 10.82 62.70 5.35 10.72                       108          C.sub.26 H.sub.28 N.sub.4 O.sub.3 S.sub.2                                                61.39 5.55 11.01 61.25 5.75 10.88                       109          C.sub.29 H.sub.32 N.sub.4 O.sub.3 S.sub.2                                                63.48 5.88 10.21 63.52 6.02 10.29                       110          C.sub.28 H.sub.30 N.sub.4 O.sub.4 S.sub.2                                                61.07 5.49 10.17 61.06 5.58 10.16                       111          C.sub.22 H.sub.26 N.sub.4 O.sub.3 S                                                      61.96 6.14 13.14 61.95 6.40 12.97                       112          C.sub.22 H.sub.26 N.sub.4 O.sub.4 S                                                      59.71 5.92 12.66 59.67 5.70 12.49                       113          C.sub.23 H.sub.30 N.sub.4 O.sub.3 S.sub.2                                                58.20 6.37 11.80 58.24 6.77 11.75                       114          C.sub.26 H.sub.36 N.sub.4 O.sub.3 S.sub.2                                                60.43 7.02 10.84 60.09 6.94 10.78                       115          C.sub.25 H.sub.34 N.sub.4 O.sub.3 S.sub.2                                                59.73 6.81 11.14 59.53 6.77 11.37                       116          C.sub.22 H.sub.27 BrN.sub.4 O.sub.3 S                                                    52.07 5.36 11.04 51.81 5.20 11.17                       117          C.sub.24 H.sub.32 N.sub.4 O.sub.3 S.sub.2                                                58.99 6.60 11.46 58.97 6.46 11.69                       118          C.sub.25 H.sub.34 N.sub.4 O.sub.3 S.sub.2                                                59.73 6.81 11.14 59.20 6.69 10.60                       __________________________________________________________________________

                                      TABLE II                                     __________________________________________________________________________                         S                    SH                                                        --COCH.sub.2 C∠                                                                   →    --CO--CH=C∠                                         SH                   SH                                    R      R.sup.1  Cryst.  Melt. P.                                                                             Formula                                                                               Calculated   Found                                        Solvent °C    C   H  N S   C   H  N S                   __________________________________________________________________________     H    3--Cl     ethyl ether                                                                             78-80 C.sub.9 H.sub.7 ClOS.sub.2                                                            46.85                                                                              3.05 27.74                                                                              46.56                                                                              2.81 27.44               H    2--CH.sub.3 O                                                                            ethyl ether                                                                             146   C.sub.10 H.sub.10 O.sub.2 S.sub.2                                                     53.10                                                                              4.46 28.28                                                                              53.30                                                                              4.18 28.47               H    3--CH.sub.3 O                                                                            ethyl ether                                                                             89-90 C.sub.10 H.sub.10 O.sub.2 S.sub.2                                                     53.10                                                                              4.46 28.28                                                                              52.93                                                                              4.11 28.16               H    4--CH.sub.3 S                                                                            ethyl ether                                                                             94    C.sub.10 H.sub.10 OS.sub.3                                                            49.55                                                                              4.16 39.69                                                                              49.35                                                                              3.87 39.50               H    4--C.sub.2 H.sub.5 S                                                                     ethyl ether                                                                             115   C.sub.11 H.sub.12 OS.sub.3                                                            51.53                                                                              4.72 37.52                                                                              51.18                                                                              4.37 37.26               H    4--n--C.sub.3 H.sub.7 S                                                                  ethyl ether                                                                             92    C.sub.12 H.sub.14 OS.sub.3                                                            53.29                                                                              5.22 35.57                                                                              53.55                                                                              5.00 35.73               H    4--i--C.sub.3 H.sub.7 S                                                                  ethyl ether                                                                             102   C.sub.12 H.sub.14 OS.sub.3                                                            53.29                                                                              5.22 35.57                                                                              53.50                                                                              5.12 35.32               H    4--n--C.sub.4 H.sub.9 S                                                                  ethyl ether                                                                             96    C.sub.13 H.sub.16 OS.sub.3                                                            54.89                                                                              5.67 33.82                                                                              54.99                                                                              5.29 33.74               H    4--i--C.sub.5 H.sub.11 S                                                                 petroleum ether                                                                         91    C.sub.14 H.sub.18 OS.sub.3                                                            56.34                                                                              6.08 32.23                                                                              56.73                                                                              6.06 32.53               H    4--n--C.sub.12 H.sub.25 S                                                                ethyl ether                                                                             59    C.sub.21 H.sub.32 OS.sub.3                                                            63.57                                                                              8.14 24.24                                                                              63.55                                                                              8.04 24.20               H    4         ethyl ether                                                                             92-93 C.sub.15 H.sub.18 OS.sub.3                                                            58.06                                                                              5.85 30.93                                                                              57.82                                                                              6.08 30.48                    S                                                                         2--Cl                                                                               4--Cl     ethyl ether                                                                             81-82 C.sub.9 H.sub.6 Cl.sub.2 OS.sub.2                                                     40.77                                                                              2.28 24.18                                                                              40.72                                                                              2.25 24.33               3--Cl                                                                               4--Cl     ethyl ether                                                                             98-99 C.sub.9 H.sub.6 Cl.sub.2 OS.sub.2                                                     40.77                                                                              2.28 24.18                                                                              40.53                                                                              2.35 23.88               2--CH.sub.3 O                                                                       4--CH.sub.3 O                                                                            ethyl ether                                                                             133   C.sub.11 H.sub.12 O.sub.3 S.sub.2                                                     51.56                                                                              4.72 24.98                                                                              51.32                                                                              4.56 24.76               __________________________________________________________________________

                                      TABLE III                                    __________________________________________________________________________                                HS                                                                             N--C∠                                                                    ∠CH.sub.2                                                                N=C                                                                  Cryst.   Melt. P.     Calculated                              R     R.sup.1    Solvent  °C                                                                            Formula                                                                               C    H   N    S    CH.sub.3             __________________________________________________________________________                                                               O                    H    2--CH.sub.3 benzene  186   C.sub.16 H.sub.14 N.sub.2 S                                                           72.16                                                                               5.30                                                                               10.52                                                                               12.02                     H    3--CH.sub.3 ethyl acetate                                                                           204   C.sub.16 H.sub.14 N.sub.2 S                                                           72.16                                                                               5.30                                                                               10.52                                                                               12.02                     H    4--CH.sub.3 ethyl acetate                                                                           243-245                                                                              C.sub.16 H.sub.14 N.sub.2 S                                                           72.16                                                                               5.30                                                                               10.52                                                                               12.02                     H    2--Cl       95% ethyl alcohol                                                                       199   C.sub.15 H.sub.11 ClN.sub.2 S                                                         62.82                                                                               3.86                                                                               9.77 11.16                     H    3--Cl       ethyl acetate                                                                           224-225                                                                              C.sub.15 H.sub.11 ClN.sub.2 S                                                         62.82                                                                               3.86                                                                               9.77 11.16                     H    2--CH.sub.3 O                                                                              methyl alcohol                                                                          195   C.sub.16 H.sub.14 N.sub.2 OS                                                          68.07                                                                               5.00                                                                               9.92 11.32                                                                               10.99                H    3--CH.sub.3 O                                                                              ethyl acetate                                                                           191   C.sub.16 H.sub.14 N.sub.2                                                             68.07                                                                               5.00                                                                               9.92 11.32                                                                               10.99                H    4--CH.sub.3 O                                                                              ethyl acetate                                                                           233 dec                                                                              C.sub.16 H.sub.14 N.sub.2 OS.sub.2                                                    68.07                                                                               5.00                                                                               9.92 11.32                                                                               10.99                H    4--CH.sub.3 S                                                                              ethyl acetate                                                                           214   C.sub.16 H.sub.14 N.sub.2 S                                                           64.42                                                                               4.73                                                                               9.39 21.46                     H    4--C.sub.2 H.sub.5 S                                                                       ethyl acetate                                                                           206   C.sub.17 H.sub.16 N.sub.2 S.sub.2                                                     65.37                                                                               5.16                                                                               8.97 20.49                     H    4--n--C.sub.3 H.sub.7 S                                                                    isopropyl alcohol                                                                       196   C.sub.18 H.sub.18 N.sub.2 S.sub.2                                                     66.24                                                                               5.56                                                                               8.58 19.61                     H    4--i--C.sub.3 H.sub.7 S                                                                    ethyl acetate                                                                           201   C.sub.18 H.sub.18 N.sub.2 S.sub.2                                                     66.24                                                                               5.56                                                                               8.58 19.61                     H    4--n--C.sub.4 H.sub.9 S                                                                    ethyl acetate                                                                           184   C.sub.19 H.sub.20 N.sub.2 S.sub.2                                                     67.04                                                                               5.92                                                                               8.23 18.80                     H    4--i--C.sub.5 H.sub.11 S                                                                   ethyl acetate                                                                           171   C.sub.20 H.sub.22 N.sub.2 S.sub.2                                                     67.78                                                                               6.26                                                                               7.91 18.06                     H    4--n--C.sub.12 H.sub.25 S                                                                  ethyl acetate                                                                           163   C.sub.27 H.sub.36 N.sub.2 S.sub.2                                                     71.63                                                                               8.01                                                                               6.19 14.26                     H    4--Br       ethyl acetate                                                                           238   C.sub.15 H.sub.11 BrN.sub.2 S                                                         54.40                                                                               3.27                                                                               8.46 9.68                      2--CH.sub.3                                                                         4--CH.sub.3 O                                                                              Benzene- 179   C.sub.17 H.sub.16 N.sub.2 O.sub.2                                                     65.36                                                                               5.16                                                                               8.97 10.30                                       petroleum ether                                              2--Cl                                                                               4--Cl       ethyl alcohol                                                                           176   C.sub.15 H.sub.10 Cl.sub.2 N.sub.2                                                    56.09                                                                               3.14                                                                               8.72  9.98                                                                               22.07+               3--Cl                                                                               4--Cl       ethyl acetate                                                                           228-229                                                                              C.sub.15 H.sub.10 Cl.sub.2 N.sub.2                                                    56.09                                                                               3.14                                                                               8.72  9.98                                                                               22.07+               H    4--CH.sub.2 S                                                                              ethyl acetate                                                                           197   C.sub.22 H.sub.18 N.sub.2 S.sub.2                                                     70.55                                                                               4.84                                                                               7.48 17.12                     H    4--S        ethyl acetate                                                                           189-190                                                                              C.sub.21 H.sub.22 N.sub.2 S.sub.2                                                     68.81                                                                               6.05                                                                               7.68 17.49                     H    2--C.sub.6 H.sub.5 S                                                                       ethyl acetate                                                                           214   C.sub.21 H.sub.16 N.sub.2 S.sub.2                                                     69.99                                                                               4.48                                                                               7.77 17.76                                                            Found                                                                          C    H   N    S    CH.sub.3             __________________________________________________________________________                                                               O                    H    2--CH.sub.3 benzene  186   C.sub.16 H.sub.14 N.sub.2 S                                                           72.65                                                                               5.42                                                                               10.64                                                                               11.68                     H    3--CH.sub.3 ethyl acetate                                                                           204   C.sub.16 H.sub.14 N.sub.2 S                                                           72.08                                                                               5.34                                                                               10.28                                                                               12.15                     H    4--CH.sub.3 ethyl acetate                                                                           243-245                                                                              C.sub.16 H.sub.14 N.sub.2 S                                                           71.56                                                                               5.26                                                                               10.38                                                                               12.30                     H    2--Cl       95% ethyl alcohol                                                                       199   C.sub.15 H.sub.11 ClN.sub.2 S                                                         62.78                                                                               3.86                                                                               9.73 11.15                     H    3--Cl       ethyl acetate                                                                           224-225                                                                              C.sub.15 H.sub.11 ClN.sub.2 S                                                         63.06                                                                               3.83                                                                               9.68 11.16                     H    2--CH.sub.3 O                                                                              methyl alcohol                                                                          195   C.sub.16 H.sub.14 N.sub.2 OS                                                          67.80                                                                               5.02                                                                               9.85 11.67                                                                               11.01                H    3--CH.sub.3 O                                                                              ethyl acetate                                                                           191   C.sub.16 H.sub.14 N.sub.2 OS                                                          68.15                                                                               4.77                                                                               9.90 11.41                                                                               10.62                H    4--CH.sub.3 O                                                                              ethyl acetate                                                                           233 dec                                                                              C.sub.16 H.sub.14 N.sub.2 OS.sub.2                                                    67.97                                                                               4.85                                                                               10.13                                                                               11.38                     H    4--CH.sub.3 S                                                                              ethyl acetate                                                                           214   C.sub.16 H.sub.14 N.sub.2 S                                                           64.78                                                                               4.40                                                                               9.47 21.36                     H    4--C.sub.2 H.sub.5 S                                                                       ethyl acetate                                                                           206   C.sub.17 H.sub.16 N.sub.2 S.sub.2                                                     65.41                                                                               5.15                                                                               8.89 20.35                     H    4--n--C.sub.3 H.sub.7 S                                                                    isopropyl alcohol                                                                       196   C.sub.18 H.sub.18 N.sub.2 S.sub.2                                                     66.30                                                                               5.42                                                                               8.45 19.36                     H    4--i--C.sub.3 H.sub.7 S                                                                    ethyl acetate                                                                           201   C.sub.18 H.sub.18 N.sub.2 S.sub.2                                                     65.86                                                                               5.24                                                                               8.30 19.70                     H    4--n--C.sub.4 H.sub.9 S                                                                    ethyl acetate                                                                           184   C.sub.19 H.sub.20 N.sub.2 S.sub.2                                                     67.17                                                                               5.93                                                                               8.09 18.91                     H    4--i--C.sub.5 H.sub.11 S                                                                   ethyl acetate                                                                           171   C.sub.20 H.sub.22 N.sub.2 S.sub.2                                                     67.62                                                                               6.18                                                                               7.99 18.03                     H    4--n--C.sub.12 H.sub.25 S                                                                  ethyl acetate                                                                           163   C.sub.27 H.sub.36 N.sub.2 S.sub.2                                                     71.99                                                                               7.94                                                                               6.31 14.22                     H    4--Br       ethyl acetate                                                                           238   C.sub.15 H.sub.11 BrN.sub.2 S                                                         54.61                                                                               3.08                                                                               8.53 9.98                      2--CH.sub.3 O                                                                       4--CH.sub.3 O                                                                              Benzene- 179   C.sub.17 H.sub.16 N.sub.2 O.sub.2                                                     65.64                                                                               4.86                                                                               9.03 10.42                                       petroleum ether                                              2--Cl                                                                               4--Cl       ethyl alcohol                                                                           176   C.sub.15 H.sub.10 Cl.sub.2 N.sub.2                                                    55.87                                                                               3.62                                                                               8.59 10.27                                                                               22.39                3--Cl                                                                               4--Cl       ethyl acetate                                                                           228-229                                                                              C.sub.15 H.sub.10 Cl.sub.2 N.sub.2                                                    55.89                                                                               2.91                                                                               8.83 10.00                                                                               21.95                H    4--CH.sub.2 S                                                                              ethyl acetate                                                                           197   C.sub.22 H.sub.18 N.sub.2 S.sub.2                                                     70.75                                                                               4.82                                                                               7.18 17.36                     H    4-- S       ethyl acetate                                                                           189-190                                                                              C.sub.21 H.sub.22 N.sub.2 S.sub.2                                                     69.11                                                                               6.21                                                                               7.68 17.28                     H    2--C.sub.6 H.sub.5 S                                                                       ethyl acetate                                                                           214   C.sub.21 H.sub.16 N.sub.2 S.sub.2                                                     69.74                                                                               4.22                                                                               7.71 17.57                     __________________________________________________________________________

ANTIBACTERIAL ACTIVITY

The antibacterial activity of some of the 3H-1,5-benzodiazepines having the general formula I was tested on the following microorganisms:

Escherichia coli 100, Bacillus subtilis ATCC 9466, Micrococcus pyogenes SG-511, grown in Difco nutritive gelatin; Streptococcus pyogenes A 88 grown in Difco "Brain heart infusion agar" gelatin with 5 percent difibrinated Guinea pig blood.

The results were read after 18 hours incubation at 35°-37°C.

The minimum inibitory concentrations ( μg/ml ) of the tested compounds are reported in table IV.

ANTIVIRAL ACTIVITY Maximal tolerated dose (MTD) in the embryonated egg

The compounds were dissolved in a saline solution buffered at a pH of 7.2 containing 500 I.U. of Penicillin G and 0.5 mg of Streptomycin/ml. Descending doses of each compound dissolved in 0.1 ml were inoculated into the allantoic sac. Each dose was injected in 3 embryonated 9-day old eggs. The highest dose which did not provoke mortality within 3 days was defined as "MTD."

ANTIVIRAL METHOD

Embryonated 9-day-old leghorn hen eggs and influenza A virus (allantoic fluid containing 10⁸ - 10⁹ EID ₅₀ (median egg-infecting dose) of egg-adapted PR8 strain) were used.

VIRUCIDAL TEST

For each dose, 0.5 MTD dissolved in 10 ml of buffered saline solution was added to 10², 10³ or 10⁴ EID₉₅ and the three solutions were kept in water bath at 37°C for 1 hour. Then, the allantoic sacs of 5 eggs (for each dose) were inoculated with 0.1 ml of one of the incubated solutions.

EVALUATION OF THE ACTIVITY

The eggs were stored at 35°C for 48 hours, then at 4°C for 10 hours and finally tested for the presence of hemoagglutinin.

RESULTS TABLE IV

The numbers in the MTD column represent the maximal tolerated doses, while those in the APR8 column represent the differences between the logarithms of EID₉₅ (eggs infecting dose) of controls and the logarithms of EID₉₅ of treated eggs.

    __________________________________________________________________________              Antibacterial activity Antiviral                                                                      activity                                                     B.sub-                                                                               M.pyo-                                                                               S.pyo-                                                                               MTD                                            No.                                                                               Salt  B. coli                                                                             tilis genes genes /coli/eggs                                                                           APR8                                     __________________________________________________________________________      9 CH.sub.3 I                                                                           --   160   160   80                                                   12 CH.sub.3 I                                                                           80   160   --    80                                                   13 HCl   80   40    40    40                                                   14 CH.sub.3 I                                                                           40   40    20    40                                                   15 HCl   80   20    40    40                                                   16 CH.sub.3 I                                                                           40   40    20    40                                                   17 HCl    80x 20    40    20x                                                  18 CH.sub.3 I                                                                            20x 20    40    10x                                                  19 HCl   80   40    40    40                                                   20 CH.sub.3 I                                                                           80   80    20    40                                                   21 HCl   80   20    40    40                                                   22 CH.sub.3 I                                                                           40   80    20    40                                                   24 CH.sub.3 I                                                                           --   --    80    --                                                   25 HCl   --   --     5x    5x                                                  26 CH.sub.3 I                                                                           --   --     5x    5x                                                  27 HCl   80   10     5x    5x                                                  28 CH.sub.3 I                                                                            40x --     5x    5x   0.3   1                                        29 HCl   80   --      5x   5x                                                  30 CH.sub.3 I                                                                           2.5x 10    1.25x 1.25x 0.3   1                                        31 PhCH.sub.2 Br                                                                        2.5x 10     0.625x                                                                               0.625x                                                                              0.3   >3                                       34 citrato                                                                              --   40    2.5x  2.5x  20    >3                                       35 CH.sub.3 I                                                                           --   10    1.25x  5x   0.15  2                                        36 2CH.sub.3 I                                                                          160  80     5x    5x                                                  37 HCl   --   5      5     5                                                   38 CH.sub.3 I                                                                           160  10    2.5   10    2.5   3                                        39 citrato                                                                              --   10     5x    5x   0.3   3                                        40 CH.sub.3 I                                                                            5x  5     1.25x  5x   0.015 1                                        41 HCl   --   10     5x   1.25x 1.25  >3                                       42 CH.sub.3 I                                                                           80   40    1.25x 1.25x 0.15  3                                        43 HCl   --   1.25   5x   1.25x                                                44 CH.sub.3 I                                                                           160  40    1.25x 1.25x 0.6   2                                        45 citrato                                                                              --   20     5x    5x                                                  46 CH.sub.3 I                                                                           160  20     5x   1.25x 0.3   2                                        48 CH.sub.3 I                                                                           80   10    1.25x 1.25x 0.6   >4                                       50 CH.sub.3 I                                                                           160  10     5x   1.25x 0.15  2                                        53 HCl   80   80    80    --                                                   57 HCl   --   160   80    80                                                   58 CH.sub.3 I                                                                           --   --          --    5     1                                        59 HCl   160  80    80    --                                                   62 CH.sub.3 I                                                                           --   --    --    --    5     1                                        63 2HCl  --   --    --    --    5     1                                        66 HCl   --   40    --    80    0.6   1                                        69 HCl   --   --    --    80                                                   74 CH.sub.3 I                                                                           40   10    20    10                                                   82 CH.sub.3 I                                                                           10   2.5   2.5   2.5   1                                              77 HCl   --   5     10     5                                                   78 CH.sub.3 I                                                                           10   1.25  1.25  1.25                                                 71 HCl   80   10    20    10                                                   72 CH.sub.3 I                                                                           20   20    10    20                                                   76 CH.sub.3 I                                                                           20   10    10    10                                                   80 CH.sub.3 I                                                                           40   5      5     5                                                   32 CH.sub.3 NO.sub.3                                                                    2.5x 10    1.25x 1.25x 0.3   1                                        __________________________________________________________________________      x in a liquid medium                                                     

In the local treatment of inflammatory and infectious diseases of the oropharynx such as tonsillitis, pharyngitis, stomatitis, alveolitis, pharyngitis secondary to rhinitis, the symptomatic treatment of influenza and treatment of pre- and post-operative conditions of the oropharynx such as tonsillectomy or tooth extraction and the like, oral administration as tablets, drops, spray, lozenges, etc. of 1-2 mg. every two to three hours is generally recommended. In long-standing cases oral administration of such an amount may be every half hour. 

What we claim is:
 1. A compound having the following formula ##EQU19## wherein R represents hydrogen, halogen, methoxy, phenylthio or alkythio group containing 1 to 12 carbon atoms;R¹ represents hydrogen, halogen, methyl, phenyl, phenoxy, alkylthio group containing 1 to 12 carbon atoms, cyclohexylthio, benzylthio or phenylthio; R² represents a dimethylamino or diethylamino group, a morpholino, piperidino pyrrolidino or 4-methylpiperazino group; and X represents an alkylene chain containing 2 or 3 carbon atoms; a salt of addition of said compound with hydrochloric acid, citric acid or tartaric acid, and a quaternary ammonium salt of said compound formed by reaction with a methyl halide, benzyl halide or methyl nitrate.
 2. Methylnitrates of 2-aminoalkylthio-3H-1,5-benzodiazepines according to claim 1 having the formula ##EQU20## wherein R, R¹, R² and X have the same meanings as in claim
 1. 3. 2,beta,N-diethylaminoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine methyl nitrate having the formula ##EQU21##
 4. 2,beta,N-diethylaminoethylthio-4,p-phenylthiophenyl-3H-1,5-benzodiazepine iodomethylate having the formula ##EQU22##
 5. The method of preparing the compound of claim 1 which comprises condensing in a solvent therefor at a temperature between 40° and 130°C. for a period ranging from 5 to 20 hours an alkaline salt of a compound having the formula ##EQU23## with a compound having the formula Hal-X-R², wherein Hal is a halogen atom and R, R¹, R² and X are as defined in claim
 1. 6. The method of preparing an acid addition salt which comprises reacting the product of the method of claim 5 with hydrochloric acid, citric acid or tartaric acid.
 7. The method of preparing a quaternary ammonium salt which comprises reacting the product of the method of claim 5 with an methyl halide, benzyl halide or methyl nitrate.
 8. The quaternary ammonium salt of claim 1 wherein the quaterization agent is methyl iodide, methyl nitrate or benzylbromide.
 9. The method of claim 5 wherein the solvent is ethyl ether, benzene or toluene.
 10. A method of preparing 2-(N-substituted)aminoalkylthio-3H-1,5-benzodiazepine methyl nitrate having the formula of claim 2 which comprises reacting in methanol at rooom temperature a 2-(N-substituted)aminoalkylthio-3H-1,5-benzodiazepine methyl ammonium iodide with silver nitrate, and removing the resulting precipitated silver iodide while the filtered methanolic solution is evaporated to dryness, to produce methylnitrate.
 11. A method of preparing 2(N-substituted)aminoalkylthio-3H-1,5-benzodiazepine methyl nitrate having the formula of claim 2, which comprises passing at room temperature for a period ranging from 1 to 4 hours a solution of 2-aminoalkylthio-3H-1,5-benzodiazepine methyl ammonium halide in 80% methanol through a column of anion exchange resin in OH form and neutralizing the resulting quaternary ammonium hydroxide methanolic solution with the theoretical quantity of nitric acid, thereafter evaporating the neutralized solution to dryness, yielding the desired methyl nitrate.
 12. An acid addition salt encompassed by claim
 1. 13. A quaternary ammonium salt encompassed by claim
 1. 14. 2,beta,N-dialkylaminoalkylene thio-4-phenyl-3H-1,5-benzodiazepine methyl nitrate, wherein dialkyl is dimethyl or diethyl and alkylene has 2 or 3 carbon atoms.
 15. 2, beta, n-dialkyl aminoalkylene thio-4-phenyl-3H-1,5-benzodiazepine iodomethylate wherein dialkyl is dimethyl or diethyl and alkylene has 2 or 3 carbon atoms. 